@article {941, title = {MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia.}, journal = {Ann Neurol}, volume = {89}, year = {2021}, month = {2021 04}, pages = {828-833}, abstract = {

The Mediator multiprotein complex functions as a regulator of RNA polymerase II-catalyzed gene transcription. In this study, exome sequencing detected biallelic putative disease-causing variants in MED27, encoding Mediator complex subunit 27, in 16 patients from 11 families with a novel neurodevelopmental syndrome. Patient phenotypes are highly homogeneous, including global developmental delay, intellectual disability, axial hypotonia with distal spasticity, dystonic movements, and cerebellar hypoplasia. Seizures and cataracts were noted in severely affected individuals. Identification of multiple patients with biallelic MED27 variants supports the critical role of MED27 in normal human neural development, particularly for the cerebellum. ANN NEUROL 2021;89:828-833.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Cataract, Cerebellum, Child, Child, Preschool, Developmental Disabilities, Dystonia, Epilepsy, Genetic Variation, Humans, Infant, Mediator Complex, Nervous System Malformations, Phenotype, Whole Exome Sequencing}, issn = {1531-8249}, doi = {10.1002/ana.26019}, author = {Meng, Linyan and Isohanni, Pirjo and Shao, Yunru and GrAHm, Brett H and Hickey, Scott E and Brooks, Stephanie and Suomalainen, Anu and Joset, Pascal and Steindl, Katharina and Rauch, Anita and Hackenberg, Annette and High, Frances A and Armstrong-Javors, Amy and Mencacci, Niccol{\`o} E and Gonz{\`a}lez-Latapi, Paulina and Kamel, Walaa A and Al-Hashel, Jasem Y and Bustos, Bernab{\'e} I and Hernandez, Alejandro V and Krainc, Dimitri and Lubbe, Steven J and Van Esch, Hilde and De Luca, Chiara and Ballon, Katleen and Ravelli, Claudia and Burglen, Lydie and Qebibo, Leila and Calame, Daniel G and Mitani, Tadahiro and Marafi, Dana and Pehlivan, Davut and Saadi, Nebal W and Sahin, Yavuz and Maroofian, Reza and Efthymiou, Stephanie and Houlden, Henry and Maqbool, Shazia and Rahman, Fatima and Gu, Shen and Posey, Jennifer E and Lupski, James R and Hunter, Jill V and Wangler, Michael F and Carroll, Christopher J and Yang, Yaping} } @article {1022, title = {POLRMT mutations impair mitochondrial transcription causing neurological disease.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 02 18}, pages = {1135}, abstract = {

While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase γ, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism.

}, keywords = {Adolescent, Adult, Child, DNA, Mitochondrial, DNA-Directed RNA Polymerases, Female, Fibroblasts, Humans, Infant, Male, Mitochondria, Mutation, Nervous System Diseases, Oxidative Phosphorylation, Pedigree, Protein Domains, Protein Subunits, RNA, Messenger, Transcription, Genetic, Young Adult}, issn = {2041-1723}, doi = {10.1038/s41467-021-21279-0}, author = {Ol{\'a}hov{\'a}, Monika and Peter, Bradley and Szilagyi, Zsolt and Diaz-Maldonado, Hector and Singh, Meenakshi and Sommerville, Ewen W and Blakely, Emma L and Collier, Jack J and Hoberg, Emily and Str{\'a}neck{\'y}, Viktor and Hartmannov{\'a}, Hana and Bleyer, Anthony J and McBride, Kim L and Bowden, Sasigarn A and Korandov{\'a}, Zuzana and Pecinov{\'a}, Alena and Ropers, Hans-Hilger and Kahrizi, Kimia and Najmabadi, Hossein and Tarnopolsky, Mark A and Brady, Lauren I and Weaver, K Nicole and Prada, Carlos E and {\~O}unap, Katrin and Wojcik, Monica H and Pajusalu, Sander and Syeda, Safoora B and Pais, Lynn and Estrella, Elicia A and Bruels, Christine C and Kunkel, Louis M and Kang, Peter B and Bonnen, Penelope E and Mr{\'a}{\v c}ek, Tom{\'a}{\v s} and Kmoch, Stanislav and Gorman, Gr{\'a}inne S and Falkenberg, Maria and Gustafsson, Claes M and Taylor, Robert W} } @article {737, title = {ASC-1 Is a Cell Cycle Regulator Associated with Severe and Mild Forms of Myopathy.}, journal = {Ann Neurol}, volume = {87}, year = {2020}, month = {2020 02}, pages = {217-232}, abstract = {

OBJECTIVE: Recently, the ASC-1 complex has been identified as a mechanistic link between amyotrophic lateral sclerosis and spinal muscular atrophy (SMA), and 3 mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations.

METHODS: Clinical, molecular, histological, and magnetic resonance imaging studies were made in 5 families with 7 novel TRIP4 mutations. Fluorescence activated cell sorting and Western blot were performed in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells.

RESULTS: All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure, and in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers, and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins, and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction.

INTERPRETATION: Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. ANN NEUROL 2020;87:217-232.

}, keywords = {Adult, Amino Acid Transport System y+, Cell Cycle, Cells, Cultured, Child, Child, Preschool, Female, Fibroblasts, Humans, Infant, Male, Middle Aged, Muscle Proteins, Muscle, Skeletal, Muscular Diseases, Mutation, Pedigree, Phenotype, Transcription Factors}, issn = {1531-8249}, doi = {10.1002/ana.25660}, author = {Villar-Quiles, Roc{\'\i}o N and Catervi, Fabio and Cabet, Eva and Juntas-Morales, Raul and Genetti, Casie A and Gidaro, Teresa and Koparir, Asuman and Yuksel, Adnan and Coppens, Sandra and Deconinck, Nicolas and Pierce-Hoffman, Emma and Lornage, Xavi{\`e}re and Durigneux, Julien and Laporte, Jocelyn and Rendu, John and Romero, Norma B and Beggs, Alan H and Servais, Laurent and Coss{\'e}e, Mireille and Oliv{\'e}, Montse and B{\"o}hm, Johann and Duband-Goulet, Isabelle and Ferreiro, Ana} } @article {758, title = {Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy.}, journal = {Ann Clin Transl Neurol}, volume = {7}, year = {2020}, month = {2020 05}, pages = {610-627}, abstract = {

OBJECTIVE: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-protein-coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families.

METHODS: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory.

RESULTS: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal- or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2~years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood.

CONCLUSION: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.

}, keywords = {Adolescent, Alleles, Atrophy, Child, Child, Preschool, Cohort Studies, Consanguinity, Epilepsy, Female, Humans, Infant, Male, Microcephaly, Neurodevelopmental Disorders, Pedigree, Phenotype, Receptors, Metabotropic Glutamate, Whole Exome Sequencing}, issn = {2328-9503}, doi = {10.1002/acn3.51003}, author = {Marafi, Dana and Mitani, Tadahiro and Isikay, Sedat and Hertecant, Jozef and Almannai, Mohammed and Manickam, Kandamurugu and Abou Jamra, Rami and El-Hattab, Ayman W and Rajah, Jaishen and Fatih, Jawid M and Du, Haowei and Karaca, Ender and Bayram, Yavuz and Punetha, Jaya and Rosenfeld, Jill A and Jhangiani, Shalini N and Boerwinkle, Eric and Akdemir, Zeynep C and Erdin, Serkan and Hunter, Jill V and Gibbs, Richard A and Pehlivan, Davut and Posey, Jennifer E and Lupski, James R} } @article {962, title = {Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 06 04}, pages = {779-792}, abstract = {

The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report bi-allelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans.

}, keywords = {Alleles, Base Sequence, Child, Child, Preschool, Cilia, Developmental Disabilities, Female, Hedgehog Proteins, Humans, Infant, Male, Models, Molecular, Neoplasms, Nerve Tissue Proteins, Nuclear Proteins, Pedigree, Signal Transduction, Smoothened Receptor, Zinc Finger Protein Gli2, Zinc Finger Protein Gli3}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.04.010}, author = {Le, Thuy-Linh and Sribudiani, Yunia and Dong, Xiaomin and Huber, Celine and Kois, Chelsea and Baujat, Genevi{\`e}ve and Gordon, Christopher T and Mayne, Valerie and Galmiche, Louise and Serre, Val{\'e}rie and Goudin, Nicolas and Zarhrate, Mohammed and Bole-Feysot, Christine and Masson, Cecile and Nitschk{\'e}, Patrick and Verheijen, Frans W and Pais, Lynn and Pelet, Anna and Sadedin, Simon and Pugh, John A and Shur, Natasha and White, Susan M and El Chehadeh, Salima and Christodoulou, John and Cormier-Daire, Val{\'e}rie and Hofstra, R M W and Lyonnet, Stanislas and Tan, Tiong Yang and Atti{\'e}-Bitach, Tania and Kerstjens-Frederikse, Wilhelmina S and Amiel, Jeanne and Thomas, Sophie} } @article {772, title = {Cytoplasmic "ciliary inclusions" in isolation are not sufficient for the diagnosis of primary ciliary dyskinesia.}, journal = {Pediatr Pulmonol}, volume = {55}, year = {2020}, month = {2020 01}, pages = {130-135}, abstract = {

BACKGROUND: The diagnosis of primary ciliary dyskinesia (PCD) is difficult and requires a combination of clinical features, nasal nitric oxide testing, cilia ultrastructural analysis by electron microscopy (EM), and genetics. A recently described cytoplasmic ultrastructural change termed "ciliary inclusions" was reported to be diagnostic of PCD; however, no supporting evidence of PCD was provided. In this study, we sought to confirm, or refute, the diagnosis of PCD in subjects with "ciliary inclusions" on EM.

METHODS: Six subjects from five families with previous lab reports of "ciliary inclusions" on EMs of ciliated cells were identified and evaluated at a Genetic Disorders of Mucociliary Clearance Consortium site. We performed a detailed clinical history, nasal nitric oxide measurement, genetic testing including whole-exome sequencing (WES), and when possible, repeat ciliary EM study.

RESULTS: Only one of six subjects had multiple and persistent clinical features congruent with PCD. No subject had situs inversus. Only one of six subjects had a very low nasal nitric oxide level. No "ciliary inclusions" were found in three subjects who had a repeat ciliary EM, and ciliary axonemal ultrastructures were normal. Genetic testing, including WES, was negative for PCD-causing genes, and for pathogenic variants in gene pathways that might cause "ciliary inclusions," such as ciliary biogenesis.

CONCLUSION: "Ciliary Inclusions", in isolation, are not sufficient to diagnosis PCD. If seen, additional studies should be done to pursue an accurate diagnosis.

}, keywords = {Child, Preschool, Cilia, Ciliary Motility Disorders, Female, Genetic Testing, Humans, Infant, Male, Nasal Mucosa, Nitric Oxide, Whole Exome Sequencing}, issn = {1099-0496}, doi = {10.1002/ppul.24528}, author = {Vece, Timothy J and Sagel, Scott D and Zariwala, Maimoona A and Sullivan, Kelli M and Burns, Kimberlie A and Dutcher, Susan K and Yusupov, Roman and Leigh, Margaret W and Knowles, Michael R} } @article {780, title = {De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 04 02}, pages = {570-583}, abstract = {

EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.

}, keywords = {Adolescent, Ataxia, Child, Child, Preschool, Developmental Disabilities, eIF-2 Kinase, Female, Genetic Variation, Hereditary Central Nervous System Demyelinating Diseases, Humans, Infant, Leukoencephalopathies, Male, Nervous System Malformations, White Matter}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.02.016}, author = {Mao, Dongxue and Reuter, Chloe M and Ruzhnikov, Maura R Z and Beck, Anita E and Farrow, Emily G and Emrick, Lisa T and Rosenfeld, Jill A and Mackenzie, Katherine M and Robak, Laurie and Wheeler, Matthew T and Burrage, Lindsay C and Jain, Mahim and Liu, Pengfei and Calame, Daniel and K{\"u}ry, S{\'e}bastien and Sillesen, Martin and Schmitz-Abe, Klaus and Tonduti, Davide and Spaccini, Luigina and Iascone, Maria and Genetti, Casie A and Koenig, Mary K and Graf, Madeline and Tran, Alyssa and Alejandro, Mercedes and Lee, Brendan H and Thiffault, Isabelle and Agrawal, Pankaj B and Bernstein, Jonathan A and Bellen, Hugo J and Chao, Hsiao-Tuan} } @article {909, title = {Deciphering congenital anomalies for the next generation.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {6}, year = {2020}, month = {2020 10}, abstract = {

Congenital anomalies are common, with 2\%-3\% of infants estimated to have at least one major congenital malformation and countless others with minor malformations of lesser cosmetic or medical importance. As congenital malformations are major drivers of morbidity and mortality, representing the leading cause of infant mortality in the United States, there is substantial interest in understanding the underlying etiologies-particularly if modifiable causes may be identified or pre- or postnatal treatments can be offered. Recent research has begun to reveal the spectrum of monogenic disorders that commonly result in birth defects, and newer approaches have revealed non-Mendelian genetic contributions including gene-environment interactions. Our experience suggests that increased efforts to sequence and analyze cases of perinatal death, as well as continued global collaboration, will be essential in understanding the genomic landscape of structural anomalies.

}, keywords = {Congenital Abnormalities, Family Characteristics, Female, Humans, Infant, Pregnancy}, issn = {2373-2873}, doi = {10.1101/mcs.a005504}, author = {Wojcik, Monica H and Agrawal, Pankaj B} } @article {738, title = {Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 01 01}, pages = {112-130}, abstract = {

The conserved transport protein particle (TRAPP) complexes regulate key trafficking events and are required for autophagy. TRAPPC4, like its yeast Trs23 orthologue, is a core component of the TRAPP complexes and one of the essential subunits for guanine nucleotide exchange factor activity for Rab1 GTPase. Pathogenic variants in specific TRAPP subunits are associated with neurological disorders. We undertook exome sequencing in three unrelated families of Caucasian, Turkish and French-Canadian ethnicities with seven affected children that showed features of early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy in an effort to determine the genetic aetiology underlying neurodevelopmental disorders. All seven affected subjects shared the same identical rare, homozygous, potentially pathogenic variant in a non-canonical, well-conserved splice site within TRAPPC4 (hg19:chr11:g.118890966A>G; TRAPPC4: NM_016146.5; c.454+3A>G). Single nucleotide polymorphism array analysis revealed there was no haplotype shared between the tested Turkish and Caucasian families suggestive of a variant hotspot region rather than a founder effect. In silico analysis predicted the variant to cause aberrant splicing. Consistent with this, experimental evidence showed both a reduction in full-length transcript levels and an increase in levels of a shorter transcript missing exon 3, suggestive of an incompletely penetrant splice defect. TRAPPC4 protein levels were significantly reduced whilst levels of other TRAPP complex subunits remained unaffected. Native polyacrylamide gel electrophoresis and size exclusion chromatography demonstrated a defect in TRAPP complex assembly and/or stability. Intracellular trafficking through the Golgi using the marker protein VSVG-GFP-ts045 demonstrated significantly delayed entry into and exit from the Golgi in fibroblasts derived from one of the affected subjects. Lentiviral expression of wild-type TRAPPC4 in these fibroblasts restored trafficking, suggesting that the trafficking defect was due to reduced TRAPPC4 levels. Consistent with the recent association of the TRAPP complex with autophagy, we found that the fibroblasts had a basal autophagy defect and a delay in autophagic flux, possibly due to unsealed autophagosomes. These results were validated using a yeast trs23 temperature sensitive variant that exhibits constitutive and stress-induced autophagic defects at permissive temperature and a secretory defect at restrictive temperature. In summary we provide strong evidence for pathogenicity of this variant in a member of the core TRAPP subunit, TRAPPC4 that associates with vesicular trafficking and autophagy defects. This is the first report of a TRAPPC4 variant, and our findings add to the growing number of TRAPP-associated neurological disorders.

}, keywords = {Atrophy, Autophagy, Cerebellum, Cerebral Cortex, Child, Child, Preschool, Craniofacial Abnormalities, Deafness, Developmental Disabilities, Epilepsy, Female, Fibroblasts, Hearing Loss, Sensorineural, Humans, Infant, Infant, Newborn, Intellectual Disability, Male, Microcephaly, Microscopy, Fluorescence, Muscle Spasticity, Nerve Tissue Proteins, Neurodevelopmental Disorders, Pedigree, Quadriplegia, RNA Splice Sites, Syndrome, Vesicular Transport Proteins}, issn = {1460-2156}, doi = {10.1093/brain/awz374}, author = {Van Bergen, Nicole J and Guo, Yiran and Al-Deri, Noraldin and Lipatova, Zhanna and Stanga, Daniela and Zhao, Sarah and Murtazina, Rakhilya and Gyurkovska, Valeriya and Pehlivan, Davut and Mitani, Tadahiro and Gezdirici, Alper and Antony, Jayne and Collins, Felicity and Willis, Mary J H and Coban Akdemir, Zeynep H and Liu, Pengfei and Punetha, Jaya and Hunter, Jill V and Jhangiani, Shalini N and Fatih, Jawid M and Rosenfeld, Jill A and Posey, Jennifer E and Gibbs, Richard A and Karaca, Ender and Massey, Sean and Ranasinghe, Thisara G and Sleiman, Patrick and Troedson, Chris and Lupski, James R and Sacher, Michael and Segev, Nava and Hakonarson, Hakon and Christodoulou, John} } @article {769, title = {Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 02 06}, pages = {234-245}, abstract = {

Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.

}, keywords = {Adult, Amino Acid Sequence, Autistic Disorder, Child, Child, Preschool, Developmental Disabilities, Dioxygenases, DNA Demethylation, Embryonic Development, Female, Gene Expression Regulation, Developmental, Growth Disorders, Humans, Infant, Male, Middle Aged, Movement Disorders, Pedigree, Protein Conformation, Sequence Homology, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.12.007}, author = {Beck, David B and Petracovici, Ana and He, Chongsheng and Moore, Hannah W and Louie, Raymond J and Ansar, Muhammad and Douzgou, Sofia and Sithambaram, Sivagamy and Cottrell, Trudie and Santos-Cortez, Regie Lyn P and Prijoles, Eloise J and Bend, Renee and Keren, Boris and Mignot, Cyril and Nougues, Marie-Christine and {\~O}unap, Katrin and Reimand, Tiia and Pajusalu, Sander and Zahid, Muhammad and Saqib, Muhammad Arif Nadeem and Buratti, Julien and Seaby, Eleanor G and McWalter, Kirsty and Telegrafi, Aida and Baldridge, Dustin and Shinawi, Marwan and Leal, Suzanne M and Schaefer, G Bradley and Stevenson, Roger E and Banka, Siddharth and Bonasio, Roberto and Fahrner, Jill A} } @article {822, title = {Gene-based analyses of the maternal genome implicate maternal effect genes as risk factors for conotruncal heart defects.}, journal = {PLoS One}, volume = {15}, year = {2020}, month = {2020}, pages = {e0234357}, abstract = {

Congenital heart defects (CHDs) affect approximately 1\% of newborns. Epidemiological studies have identified several genetically-mediated maternal phenotypes (e.g., pregestational diabetes, chronic hypertension) that are associated with the risk of CHDs in offspring. However, the role of the maternal genome in determining CHD risk has not been defined. We present findings from gene-level, genome-wide studies that link CHDs to maternal effect genes as well as to maternal genes related to hypertension and proteostasis. Maternal effect genes, which provide the mRNAs and proteins in the oocyte that guide early embryonic development before zygotic gene activation, have not previously been implicated in CHD risk. Our findings support a role for and suggest new pathways by which the maternal genome may contribute to the development of CHDs in offspring.

}, keywords = {Adult, Case-Control Studies, Child, Preschool, Family, Female, Genetic Testing, Heart Defects, Congenital, Humans, Hypertension, Infant, Infant, Newborn, Male, Maternal Exposure, Maternal Inheritance, Middle Aged, Oocytes, Pregnancy, Prenatal Exposure Delayed Effects, Proteostasis, Risk Factors}, issn = {1932-6203}, doi = {10.1371/journal.pone.0234357}, author = {Sewda, Anshuman and Agopian, A J and Goldmuntz, Elizabeth and Hakonarson, Hakon and Morrow, Bernice E and Musfee, Fadi and Taylor, Deanne and Mitchell, Laura E} } @article {846, title = {Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort.}, journal = {Epilepsia}, volume = {61}, year = {2020}, month = {2020 02}, pages = {249-258}, abstract = {

OBJECTIVE: We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well-phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology.

METHODS: We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection-related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing.

RESULTS: Overall, we identified pathogenic or likely pathogenic variants in 40\% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy-related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26\% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25\%).

SIGNIFICANCE: Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well-phenotyped patients with epilepsy leads to a broader understanding of gene-specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease-associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.

}, keywords = {Adolescent, Adult, Age of Onset, Brain Diseases, Child, Child, Preschool, Chromosomes, Human, Cohort Studies, Epilepsy, Epilepsy, Generalized, Exome, Female, Genetic Testing, Genetic Variation, Humans, Infant, Male, Microarray Analysis, Phenotype, Whole Exome Sequencing, Young Adult}, issn = {1528-1167}, doi = {10.1111/epi.16427}, author = {Rochtus, Anne and Olson, Heather E and Smith, Lacey and Keith, Louisa G and El Achkar, Christelle and Taylor, Alan and Mahida, Sonal and Park, Meredith and Kelly, McKenna and Shain, Catherine and Rockowitz, Shira and Rosen Sheidley, Beth and Poduri, Annapurna} } @article {937, title = {Human NK cell deficiency as a result of biallelic mutations in MCM10.}, journal = {J Clin Invest}, volume = {130}, year = {2020}, month = {2020 10 01}, pages = {5272-5286}, abstract = {

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage-response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.

}, keywords = {Alleles, Cell Cycle Checkpoints, Cell Differentiation, Cell Line, Codon, Nonsense, DNA Damage, Fatal Outcome, Female, Gene Knockdown Techniques, Heterozygote, Humans, Induced Pluripotent Stem Cells, Infant, Killer Cells, Natural, Male, Minichromosome Maintenance Proteins, Models, Immunological, Mutation, Mutation, Missense, Pedigree, Primary Immunodeficiency Diseases}, issn = {1558-8238}, doi = {10.1172/JCI134966}, author = {Mace, Emily M and Paust, Silke and Conte, Matilde I and Baxley, Ryan M and Schmit, Megan M and Patil, Sagar L and Guilz, Nicole C and Mukherjee, Malini and Pezzi, Ashley E and Chmielowiec, Jolanta and Tatineni, Swetha and Chinn, Ivan K and Akdemir, Zeynep Coban and Jhangiani, Shalini N and Muzny, Donna M and Stray-Pedersen, Asbj{\o}rg and Bradley, Rachel E and Moody, Mo and Connor, Philip P and Heaps, Adrian G and Steward, Colin and Banerjee, Pinaki P and Gibbs, Richard A and Borowiak, Malgorzata and Lupski, James R and Jolles, Stephen and Bielinsky, Anja K and Orange, Jordan S} } @article {903, title = {Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.}, journal = {Science}, volume = {370}, year = {2020}, month = {2020 10 23}, abstract = {

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5\%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Asymptomatic Infections, Betacoronavirus, Child, Child, Preschool, Coronavirus Infections, COVID-19, Female, Genetic Loci, Genetic Predisposition to Disease, Humans, Infant, Interferon Regulatory Factor-7, Interferon Type I, Loss of Function Mutation, Male, Middle Aged, Pandemics, Pneumonia, Viral, Receptor, Interferon alpha-beta, SARS-CoV-2, Toll-Like Receptor 3, Young Adult}, issn = {1095-9203}, doi = {10.1126/science.abd4570}, author = {Zhang, Qian and Bastard, Paul and Liu, Zhiyong and Le Pen, J{\'e}r{\'e}mie and Moncada-Velez, Marcela and Chen, Jie and Ogishi, Masato and Sabli, Ira K D and Hodeib, Stephanie and Korol, Cecilia and Rosain, J{\'e}r{\'e}mie and Bilguvar, Kaya and Ye, Junqiang and Bolze, Alexandre and Bigio, Benedetta and Yang, Rui and Arias, Andr{\'e}s Augusto and Zhou, Qinhua and Zhang, Yu and Onodi, Fanny and Korniotis, Sarantis and Karpf, L{\'e}a and Philippot, Quentin and Chbihi, Marwa and Bonnet-Madin, Lucie and Dorgham, Karim and Smith, Nika{\"\i}a and Schneider, William M and Razooky, Brandon S and Hoffmann, Hans-Heinrich and Michailidis, Eleftherios and Moens, Leen and Han, Ji Eun and Lorenzo, Lazaro and Bizien, Lucy and Meade, Philip and Neehus, Anna-Lena and Ugurbil, Aileen Camille and Corneau, Aur{\'e}lien and Kerner, Gaspard and Zhang, Peng and Rapaport, Franck and Seeleuthner, Yoann and Manry, Jeremy and Masson, Cecile and Schmitt, Yohann and Schluter, Agatha and Le Voyer, Tom and Khan, Taushif and Li, Juan and Fellay, Jacques and Roussel, Lucie and Shahrooei, Mohammad and Alosaimi, Mohammed F and Mansouri, Davood and Al-Saud, Haya and Al-Mulla, Fahd and Almourfi, Feras and Al-Muhsen, Saleh Zaid and Alsohime, FAHd and Al Turki, Saeed and Hasanato, Rana and van de Beek, Diederik and Biondi, Andrea and Bettini, Laura Rachele and D{\textquoteright}Angio{\textquoteright}, Mariella and Bonfanti, Paolo and Imberti, Luisa and Sottini, Alessandra and Paghera, Simone and Quiros-Roldan, Eugenia and Rossi, Camillo and Oler, Andrew J and Tompkins, Miranda F and Alba, Camille and Vandernoot, Isabelle and Goffard, Jean-Christophe and Smits, Guillaume and Migeotte, Isabelle and Haerynck, Filomeen and Soler-Palacin, Pere and Martin-Nalda, Andrea and Colobran, Roger and Morange, Pierre-Emmanuel and Keles, Sevgi and {\c C}{\"o}lkesen, Fatma and Ozcelik, Tayfun and Yasar, Kadriye Kart and Senoglu, Sevtap and Karabela, {\c S}emsi Nur and Rodr{\'\i}guez-Gallego, Carlos and Novelli, Giuseppe and Hraiech, Sami and Tandjaoui-Lambiotte, Yacine and Duval, Xavier and Laou{\'e}nan, C{\'e}dric and Snow, Andrew L and Dalgard, Clifton L and Milner, Joshua D and Vinh, Donald C and Mogensen, Trine H and Marr, Nico and Spaan, Andr{\'a}s N and Boisson, Bertrand and Boisson-Dupuis, St{\'e}phanie and Bustamante, Jacinta and Puel, Anne and Ciancanelli, Michael J and Meyts, Isabelle and Maniatis, Tom and Soumelis, Vassili and Amara, Ali and Nussenzweig, Michel and Garc{\'\i}a-Sastre, Adolfo and Krammer, Florian and Pujol, Aurora and Duffy, Darragh and Lifton, Richard P and Zhang, Shen-Ying and Gorochov, Guy and B{\'e}ziat, Vivien and Jouanguy, Emmanuelle and Sancho-Shimizu, Vanessa and Rice, Charles M and Abel, Laurent and Notarangelo, Luigi D and Cobat, Aurelie and Su, Helen C and Casanova, Jean-Laurent} } @article {647, title = {Inherited glomerular diseases in the gilded age of genomic advancements.}, journal = {Pediatr Nephrol}, volume = {35}, year = {2020}, month = {2020 06}, pages = {959-968}, abstract = {

The synchronized advent of high-throughput next-generation sequencing technology and knowledge of the human genome has rendered exponential contributions to our understanding of the pathophysiology of glomerular kidney diseases. A genetic diagnosis can now be made or confirmed in about two-thirds of the suspected inherited glomerular diseases. Next-generation sequencing is adept at identifying single nucleotide variations and small insertions or deletions that constitute majority of the disease-causing mutations. Description of the complete mutation spectrum in syndromic glomerulopathies may require the use of both sequencing and cytogenetic methods to detect large structural DNA variation in addition to single nucleotide changes. The enthusiastic application of genetic and genomic knowledge to inherited glomerular diseases has uncovered anticipated and unforeseen challenges mainly related to the biological interpretation of variants of uncertain significance and the limited benefit on clinical management for the individual patient when a diagnosis is obtained. To attain the ultimate goal of transforming clinical decision-making based on accurate genetic diagnosis using genomic information, these challenges need to be addressed. Till then, the glory of genomic medicine stands the test of time in this gilded age of genomic advancements.

}, keywords = {Adolescent, Age Factors, Branchio-Oto-Renal Syndrome, Child, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Kidney Failure, Chronic, Male, Middle Aged, Mutation, Pedigree, Polymorphism, Single Nucleotide, Renal Insufficiency, Chronic, Whole Exome Sequencing}, issn = {1432-198X}, doi = {10.1007/s00467-019-04266-y}, author = {Gulati, Ashima and Dahl, Neera and Tufro, Alda} } @article {770, title = {MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 01 01}, pages = {55-68}, abstract = {

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3{\textquoteright} region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

}, keywords = {Abnormalities, Multiple, Adolescent, Basilar Artery, Carotid Arteries, Cerebellar Vermis, Cerebellum, Child, Child, Preschool, Cohort Studies, Comparative Genomic Hybridization, Craniofacial Abnormalities, Female, Fibroblasts, Humans, Imaging, Three-Dimensional, Infant, Intellectual Disability, Language Development Disorders, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Nervous System Malformations, Nonsense Mediated mRNA Decay, Polymicrogyria, Real-Time Polymerase Chain Reaction, RNA-Seq, Syndrome, Tomography, X-Ray Computed, Trans-Activators, Tumor Suppressor Proteins, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {1460-2156}, doi = {10.1093/brain/awz379}, author = {Mak, Christopher C Y and Doherty, Dan and Lin, Angela E and Vegas, Nancy and Cho, Megan T and Viot, G{\'e}raldine and Dimartino, Cl{\'e}mantine and Weisfeld-Adams, James D and Lessel, Davor and Joss, Shelagh and Li, Chumei and Gonzaga-Jauregui, Claudia and Zarate, Yuri A and Ehmke, Nadja and Horn, Denise and Troyer, Caitlin and Kant, Sarina G and Lee, Youngha and Ishak, Gisele E and Leung, Gordon and Barone Pritchard, Amanda and Yang, Sandra and Bend, Eric G and Filippini, Francesca and Roadhouse, Chelsea and Lebrun, Nicolas and Mehaffey, Michele G and Martin, Pierre-Marie and Apple, Benjamin and Millan, Francisca and Puk, Oliver and Hoffer, Mariette J V and Henderson, Lindsay B and McGowan, Ruth and Wentzensen, Ingrid M and Pei, Steven and Zahir, Farah R and Yu, Mullin and Gibson, William T and Seman, Ann and Steeves, Marcie and Murrell, Jill R and Luettgen, Sabine and Francisco, Elizabeth and Strom, Tim M and Amlie-Wolf, Louise and Kaindl, Angela M and Wilson, William G and Halbach, Sara and Basel-Salmon, Lina and Lev-El, Noa and Denecke, Jonas and Vissers, Lisenka E L M and Radtke, Kelly and Chelly, Jamel and Zackai, Elaine and Friedman, Jan M and Bamshad, Michael J and Nickerson, Deborah A and Reid, Russell R and Devriendt, Koenraad and Chae, Jong-Hee and Stolerman, Elliot and McDougall, Carey and Powis, Z{\"o}e and Bienvenu, Thierry and Tan, Tiong Y and Orenstein, Naama and Dobyns, William B and Shieh, Joseph T and Choi, Murim and Waggoner, Darrel and Gripp, Karen W and Parker, Michael J and Stoler, Joan and Lyonnet, Stanislas and Cormier-Daire, Val{\'e}rie and Viskochil, David and Hoffman, Trevor L and Amiel, Jeanne and Chung, Brian H Y and Gordon, Christopher T} } @article {826, title = {Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families.}, journal = {BMC Med Genomics}, volume = {13}, year = {2020}, month = {2020 05 13}, pages = {68}, abstract = {

BACKGROUND: The causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease.

METHODS: Retrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease.

RESULTS: Between 2010 and 2016, 1172 families presented with a child a likely~rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation~in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive~for~the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older~affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25\% to the observed 12\% ([95\% CI 0{\textperiodcentered}04 to 0{\textperiodcentered}20], p = 0{\textperiodcentered}011).

CONCLUSIONS: Molecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence.

}, keywords = {Child, Preschool, Female, Genes, Recessive, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genotype, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Male, Mutation, Nervous System Diseases, Pedigree, Pregnancy, Prenatal Diagnosis, Recurrence, Retrospective Studies}, issn = {1755-8794}, doi = {10.1186/s12920-020-0714-1}, author = {Issa, Mahmoud Y and Chechlacz, Zinayida and Stanley, Valentina and George, Renee D and McEvoy-Venneri, Jennifer and Belandres, Denice and Elbendary, Hasnaa M and Gaber, Khaled R and Nabil, Ahmed and Abdel-Hamid, Mohamed S and Zaki, MAH S and Gleeson, Joseph G} } @article {906, title = {Monogenic variants in dystonia: an exome-wide sequencing study.}, journal = {Lancet Neurol}, volume = {19}, year = {2020}, month = {2020 11}, pages = {908-918}, abstract = {

BACKGROUND: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.

METHODS: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow.

FINDINGS: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19\%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45\%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19\%] of 98) or isolated (16 [4\%] of 388) dystonia. Across all categories of dystonia, 104 (65\%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism.

INTERPRETATION: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations.

FUNDING: Else Kr{\"o}ner-Fresenius-Stiftung, Technische Universit{\"a}t M{\"u}nchen, Helmholtz Zentrum M{\"u}nchen, Medizinische Universit{\"a}t Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

}, keywords = {Adolescent, Child, Child, Preschool, Dystonia, Exome, Female, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Pedigree, Whole Exome Sequencing, Young Adult}, issn = {1474-4465}, doi = {10.1016/S1474-4422(20)30312-4}, author = {Zech, Michael and Jech, Robert and Boesch, Sylvia and {\v S}korv{\'a}nek, Matej and Weber, Sandrina and Wagner, Matias and Zhao, Chen and Jochim, Angela and Necp{\'a}l, J{\'a}n and Dincer, Yasemin and Vill, Katharina and Distelmaier, Felix and Stoklosa, Malgorzata and Krenn, Martin and Grunwald, Stephan and Bock-Bierbaum, Tobias and Fe{\v c}{\'\i}kov{\'a}, Anna and Havr{\'a}nkov{\'a}, Petra and Roth, Jan and P{\v r}{\'\i}hodov{\'a}, Iva and Adamovi{\v c}ov{\'a}, Miriam and Ulmanov{\'a}, Olga and Bechyn{\v e}, Karel and Danhofer, Pavl{\'\i}na and Vesel{\'y}, Branislav and Ha{\v n}, Vladim{\'\i}r and Pavelekova, Petra and Gdovinov{\'a}, Zuzana and Mantel, Tobias and Meindl, Tobias and Sitzberger, Alexandra and Schr{\"o}der, Sebastian and Blaschek, Astrid and Roser, Timo and Bonfert, Michaela V and Haberlandt, Edda and Plecko, Barbara and Leineweber, Birgit and Berweck, Steffen and Herberhold, Thomas and Langguth, Berthold and {\v S}vantnerov{\'a}, Jana and Min{\'a}r, Michal and Ramos-Rivera, Gonzalo Alonso and Wojcik, Monica H and Pajusalu, Sander and {\~O}unap, Katrin and Schatz, Ulrich A and P{\"o}lsler, Laura and Milenkovic, Ivan and Laccone, Franco and Pilshofer, Veronika and Colombo, Roberto and Patzer, Steffi and Iuso, Arcangela and Vera, Julia and Troncoso, Monica and Fang, Fang and Prokisch, Holger and Wilbert, Friederike and Eckenweiler, Matthias and Graf, Elisabeth and Westphal, Dominik S and Riedhammer, Korbinian M and Brunet, Theresa and Alhaddad, Bader and Berutti, Riccardo and Strom, Tim M and Hecht, Martin and Baumann, Matthias and Wolf, Marc and Telegrafi, Aida and Person, Richard E and Zamora, Francisca Millan and Henderson, Lindsay B and Weise, David and Musacchio, Thomas and Volkmann, Jens and Szuto, Anna and Becker, Jessica and Cremer, Kirsten and Sycha, Thomas and Zimprich, Fritz and Kraus, Verena and Makowski, Christine and Gonzalez-Alegre, Pedro and Bardakjian, Tanya M and Ozelius, Laurie J and Vetro, Annalisa and Guerrini, Renzo and Maier, Esther and Borggraefe, Ingo and Kuster, Alice and Wortmann, Saskia B and Hackenberg, Annette and Steinfeld, Robert and Assmann, Birgit and Staufner, Christian and Opladen, Thomas and R{\r u}{\v z}i{\v c}ka, Ev{\v z}en and Cohn, Ronald D and Dyment, David and Chung, Wendy K and Engels, Hartmut and Ceballos-Baumann, Andres and Ploski, Rafal and Daumke, Oliver and Haslinger, Bernhard and Mall, Volker and Oexle, Konrad and Winkelmann, Juliane} } @article {907, title = {Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 10 01}, pages = {727-742}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X.~tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

}, keywords = {Amphibian Proteins, Animals, Case-Control Studies, Child, Child, Preschool, DNA-Binding Proteins, Epigenesis, Genetic, Family, Female, Forkhead Transcription Factors, Heterozygote, Humans, Infant, Larva, Male, Mice, Mice, Knockout, Morpholinos, Mutation, Pedigree, Protein Binding, Repressor Proteins, Transcription Factors, Urinary Tract, Urogenital Abnormalities, Whole Exome Sequencing, Xenopus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.08.013}, author = {Connaughton, Dervla M and Dai, Rufeng and Owen, Danielle J and Marquez, Jonathan and Mann, Nina and GrAHm-Paquin, Adda L and Nakayama, Makiko and Coyaud, Etienne and Laurent, Estelle M N and St-Germain, Jonathan R and Blok, Lot Snijders and Vino, Arianna and Kl{\"a}mbt, Verena and Deutsch, Konstantin and Wu, Chen-Han Wilfred and Kolvenbach, Caroline M and Kause, Franziska and Ottlewski, Isabel and Schneider, Ronen and Kitzler, Thomas M and Majmundar, Amar J and Buerger, Florian and Onuchic-Whitford, Ana C and Youying, Mao and Kolb, Amy and Salmanullah, Daanya and Chen, Evan and van der Ven, Amelie T and Rao, Jia and Ityel, Hadas and Seltzsam, Steve and Rieke, Johanna M and Chen, Jing and Vivante, Asaf and Hwang, Daw-Yang and Kohl, Stefan and Dworschak, Gabriel C and Hermle, Tobias and Alders, Marielle and Bartolomaeus, Tobias and Bauer, Stuart B and Baum, Michelle A and Brilstra, Eva H and Challman, Thomas D and Zyskind, Jacob and Costin, Carrie E and Dipple, Katrina M and Duijkers, Floor A and Ferguson, Marcia and FitzPatrick, David R and Fick, Roger and Glass, Ian A and Hulick, Peter J and Kline, Antonie D and Krey, Ilona and Kumar, Selvin and Lu, Weining and Marco, Elysa J and Wentzensen, Ingrid M and Mefford, Heather C and Platzer, Konrad and Povolotskaya, Inna S and Savatt, Juliann M and Shcherbakova, Natalia V and Senguttuvan, Prabha and Squire, Audrey E and Stein, Deborah R and Thiffault, Isabelle and Voinova, Victoria Y and Somers, Michael J G and Ferguson, Michael A and Traum, Avram Z and Daouk, Ghaleb H and Daga, Ankana and Rodig, Nancy M and Terhal, Paulien A and van Binsbergen, Ellen and Eid, Loai A and Tasic, Velibor and Rasouly, Hila Milo and Lim, Tze Y and Ahram, Dina F and Gharavi, Ali G and Reutter, Heiko M and Rehm, Heidi L and MacArthur, Daniel G and Lek, Monkol and Laricchia, Kristen M and Lifton, Richard P and Xu, Hong and Mane, Shrikant M and Sanna-Cherchi, Simone and Sharrocks, Andrew D and Raught, Brian and Fisher, Simon E and Bouchard, Maxime and Khokha, Mustafa K and Shril, Shirlee and Hildebrandt, Friedhelm} } @article {938, title = {Natural history of Ollier disease and Maffucci syndrome: Patient survey and review of clinical literature.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 05}, pages = {1093-1103}, abstract = {

Ollier disease (OD) and Maffucci syndrome (MS) are characterized by multiple enchondromas. Patients with MS also have benign vascular overgrowths that become malignant in 8.5\% of cases. OD is characterized by multiple enchondromas, typically unilateral in distribution with a predilection for the appendicular skeleton. MS is characterized by multiple enchondromas bilaterally distributed in most of the cases. Both disorders feature multiple swellings on the extremity, deformity around the joints, limitations in joint mobility, scoliosis, bone shortening, leg-length discrepancy, gait disturbances, pain, loss of function, and pathological fractures. About 50\% of patients with OD or MS develop a malignancy, such as chondrosarcoma, glioma, and ovarian juvenile granulosa cell tumor. To better understand the natural history of OD and MS, we reviewed 287 papers describing patients with OD and MS. We also created a survey that was distributed directly to 162 patients through Facebook. Here, we compare the review of the cases described in the literature to the survey{\textquoteright}s responses. The review of the literature showed that: the patients with OD are diagnosed at a younger age; the prevalence of chondrosarcomas among patients with OD or MS was ~30\%; in four patients, vascular anomalies were identified in internal organs only; and, the prevalence of cancer among patients with OD or MS was ~50\%. With these data, health care providers will better understand the natural history, severity, and prognosis of these diseases and the prevalence of malignancies in these patients. Here, we recommend new guidelines for the care of patients with OD and MS.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chondrosarcoma, Enchondromatosis, Female, Granulosa Cell Tumor, Humans, Infant, Infant, Newborn, Male, Middle Aged, Ovarian Neoplasms, Prognosis, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61530}, author = {El Abiad, Jad M and Robbins, Sarah M and Cohen, Bernard and Levin, Adam S and Valle, David L and Morris, Carol D and de Macena Sobreira, Nara L} } @article {852, title = {Next Generation Sequencing of 134 Children with Autism Spectrum Disorder and Regression.}, journal = {Genes (Basel)}, volume = {11}, year = {2020}, month = {2020 07 25}, abstract = {

Approximately 30\% of individuals with autism spectrum disorder (ASD) experience developmental regression, the etiology of which remains largely unknown. We performed a complete literature search and identified 47 genes that had been implicated in such cases. We sequenced these genes in a preselected cohort of 134 individuals with regressive autism. In total, 16 variants in 12 genes with evidence supportive of pathogenicity were identified. They were classified as variants of uncertain significance based on ACMG standards and guidelines. Among these were recurring variants in and , variants in genes that were linked to syndromic forms of ASD (, , , , , and ), and variants in the form of oligogenic heterozygosity (, , and ).

}, keywords = {Autism Spectrum Disorder, Child, Child, Preschool, Cohort Studies, Disease Progression, Female, Gene Expression Regulation, Genetic Markers, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Infant, Male, Mutation}, issn = {2073-4425}, doi = {10.3390/genes11080853}, author = {Yin, Jiani and Chun, Chun-An and Zavadenko, Nikolay N and Pechatnikova, Natalia L and Naumova, Oxana Yu and Doddapaneni, Harsha V and Hu, Jianhong and Muzny, Donna M and Schaaf, Christian P and Grigorenko, Elena L} } @article {910, title = {Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.}, journal = {Neuron}, volume = {106}, year = {2020}, month = {2020 04 22}, pages = {237-245.e8}, abstract = {

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1~(also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of~posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.

}, keywords = {Adolescent, Adult, Age of Onset, Animals, Centrosome, Child, Child, Preschool, Chromosome Aberrations, Classical Lissencephalies and Subcortical Band Heterotopias, Cytoskeletal Proteins, Female, Gene Knockdown Techniques, Genetic Variation, Heterozygote, Humans, Infant, Magnetic Resonance Imaging, Male, Mice, Mutation, Oncogene Proteins, Fusion, Pedigree, Seizures, Young Adult}, issn = {1097-4199}, doi = {10.1016/j.neuron.2020.01.027}, author = {Tsai, Meng-Han and Muir, Alison M and Wang, Won-Jing and Kang, Yi-Ning and Yang, Kun-Chuan and Chao, Nian-Hsin and Wu, Mei-Feng and Chang, Ying-Chao and Porter, Brenda E and Jansen, Laura A and Sebire, Guillaume and Deconinck, Nicolas and Fan, Wen-Lang and Su, Shih-Chi and Chung, Wen-Hung and Almanza Fuerte, Edith P and Mehaffey, Michele G and Ng, Ching-Ching and Chan, Chung-Kin and Lim, Kheng-Seang and Leventer, Richard J and Lockhart, Paul J and Riney, Kate and Damiano, John A and Hildebrand, Michael S and Mirzaa, Ghayda M and Dobyns, William B and Berkovic, Samuel F and Scheffer, Ingrid E and Tsai, Jin-Wu and Mefford, Heather C} } @article {707, title = {Phenotypic expansion of POGZ-related intellectual disability syndrome (White-Sutton syndrome).}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 01}, pages = {38-52}, abstract = {

White-Sutton syndrome (WHSUS) is a recently-identified genetic disorder resulting from de novo heterozygous pathogenic variants in POGZ. Thus far, over 50 individuals have been reported worldwide, however phenotypic characterization and data regarding the natural history are still incomplete. Here we report the clinical features of 22 individuals with 21 unique loss of function POGZ variants. We observed a broad spectrum of intellectual disability and/or developmental delay with or without autism, and speech delay in all individuals. Other common problems included ocular abnormalities, hearing loss and gait abnormalities. A validated sleep disordered breathing questionnaire identified symptoms of obstructive sleep apnea in 4/12 (33\%) individuals. A higher-than-expected proportion of cases also had gastrointestinal phenotypes, both functional and anatomical, as well as genitourinary anomalies. In line with previous publications, we observed an increased body mass index (BMI) z-score compared to the general population (mean 0.59, median 0.9; p 0.0253). Common facial features included microcephaly, broad forehead, midface hypoplasia, triangular mouth, broad nasal root and flat nasal bridge. Analysis of the Baylor Genetics clinical laboratory database revealed that POGZ variants were implicated in approximately 0.14\% of cases who underwent clinical exome sequencing for neurological indications with or without involvement of other body systems. This study describes a greater allelic series and expands the phenotypic spectrum of this new syndromic form of intellectual disability and autism.

}, keywords = {Adolescent, Adult, Autistic Disorder, Child, Child, Preschool, Exome, Female, Heterozygote, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Microcephaly, Middle Aged, Mutation, Phenotype, Transposases, Whole Exome Sequencing, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61380}, author = {Assia Batzir, Nurit and Posey, Jennifer E and Song, Xiaofei and Akdemir, Zeynep Coban and Rosenfeld, Jill A and Brown, Chester W and Chen, Emily and Holtrop, Shannon G and Mizerik, Elizabeth and Nieto Moreno, Margarita and Payne, Katelyn and Raas-Rothschild, Annick and Scott, Richard and Vernon, Hilary J and Zadeh, Neda and Lupski, James R and Sutton, V Reid} } @article {940, title = {Polymicrogyria is Associated With Pathogenic Variants in PTEN.}, journal = {Ann Neurol}, volume = {88}, year = {2020}, month = {2020 12}, pages = {1153-1164}, abstract = {

OBJECTIVE: Congenital structural brain malformations have been described in patients with pathogenic phosphatase and tensin homologue (PTEN) variants, but the frequency of cortical malformations in patients with PTEN variants and their impact on clinical phenotype are not well understood. Our goal was to systematically characterize brain malformations in patients with PTEN variants and assess the relevance of their brain malformations to clinical presentation.

METHODS: We systematically searched a local radiology database for patients with PTEN variants who had available brain magnetic resonance imaging (MRI). The MRI scans were reviewed systematically for cortical abnormalities. We reviewed electroencephalogram (EEG) data and evaluated the electronic medical record for evidence of epilepsy and developmental delay.

RESULTS: In total, we identified 22 patients with PTEN pathogenic variants for which brain MRIs were available (age range 0.4-17 years). Twelve among these 22 patients (54\%) had polymicrogyria (PMG). Variants associated with PMG or atypical gyration encoded regions of the phosphatase or C2 domains of PTEN. Interestingly, epilepsy was present in only 2 of the 12 patients with PMG. We found a trend toward higher rates of global developmental delay (GDD), intellectual disability (ID), and motor delay in individuals with cortical abnormalities, although cohort size limited statistical significance.

INTERPRETATION: Malformations of cortical development, PMG in particular, represent an under-recognized phenotype associated with PTEN pathogenic variants and may have an association with cognitive and motor delays. Epilepsy was infrequent compared to the previously reported high risk of epilepsy in patients with PMG. ANN NEUROL 2020;88:1153-1164.

}, keywords = {Adolescent, Brain, Child, Child, Preschool, Comorbidity, Databases, Genetic, Developmental Disabilities, Electroencephalography, Female, Humans, Infant, Intellectual Disability, Magnetic Resonance Imaging, Male, Massachusetts, Neuroimaging, Polymicrogyria, PTEN Phosphohydrolase}, issn = {1531-8249}, doi = {10.1002/ana.25904}, author = {Shao, Diane D and Achkar, Christelle M and Lai, Abbe and Srivastava, Siddharth and Doan, Ryan N and Rodan, Lance H and Chen, Allen Y and Poduri, Annapurna and Yang, Edward and Walsh, Christopher A} } @article {767, title = {Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 02 06}, pages = {272-279}, abstract = {

Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data.

}, keywords = {Amino Acid Sequence, ATPases Associated with Diverse Cellular Activities, Brain Diseases, Cardiomyopathies, Cholesterol, Corneal Opacity, DNA Copy Number Variations, Female, Gene Duplication, Gene Rearrangement, Homologous Recombination, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Mitochondria, Mitochondrial Diseases, Mitochondrial Proteins, Muscle Hypotonia, Mutation, Protein Conformation, Seizures, Sequence Homology}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.01.007}, author = {Gunning, Adam C and Strucinska, Klaudia and Mu{\~n}oz Oreja, Mikel and Parrish, Andrew and Caswell, Richard and Stals, Karen L and Durigon, Romina and Durlacher-Betzer, Karina and Cunningham, Mitchell H and Grochowski, Christopher M and Baptista, Julia and Tysoe, Carolyn and Baple, Emma and Lahiri, Nayana and Homfray, Tessa and Scurr, Ingrid and Armstrong, Catherine and Dean, John and Fernandez Pelayo, Uxoa and Jones, Aleck W E and Taylor, Robert W and Misra, Vinod K and Yoon, Wan Hee and Wright, Caroline F and Lupski, James R and Spinazzola, Antonella and Harel, Tamar and Holt, Ian J and Ellard, Sian} } @article {805, title = {Recurrent Rare Copy Number Variants Increase Risk for Esotropia.}, journal = {Invest Ophthalmol Vis Sci}, volume = {61}, year = {2020}, month = {2020 08 03}, pages = {22}, abstract = {

Purpose: To determine whether rare copy number variants (CNVs) increase risk for comitant esotropia.

Methods: CNVs were identified in 1614 Caucasian individuals with comitant esotropia and 3922 Caucasian controls from Illumina SNP genotyping using two Hidden Markov model (HMM) algorithms, PennCNV and QuantiSNP, which call CNVs based on logR ratio and B allele frequency. Deletions and duplications greater than 10 kb were included. Common CNVs were excluded. Association testing was performed with 1 million permutations in PLINK. Significant CNVs were confirmed with digital droplet polymerase chain reaction (ddPCR). Whole genome sequencing was performed to determine insertion location and breakpoints.

Results: Esotropia patients have similar rates and proportions of CNVs compared with controls but greater total length and average size of both deletions and duplications. Three recurrent rare duplications significantly (P = 1 {\texttimes} 10-6) increase the risk of esotropia: chromosome 2p11.2 (hg19, 2:87428677-87965359), spanning one long noncoding RNA (lncRNA) and two microRNAs (OR 14.16; 95\% confidence interval [CI] 5.4-38.1); chromosome 4p15.2 (hg19, 4:25554332-25577184), spanning one lncRNA (OR 11.1; 95\% CI 4.6-25.2); chromosome 10q11.22 (hg19, 10:47049547-47703870) spanning seven protein-coding genes, one lncRNA, and four pseudogenes (OR 8.96; 95\% CI 5.4-14.9). Overall, 114 cases (7\%) and only 28 controls (0.7\%) had one of the three rare duplications. No case nor control had more than one of these three duplications.

Conclusions: Rare CNVs are a source of genetic variation that contribute to the genetic risk for comitant esotropia, which is likely polygenic. Future research into the functional consequences of these recurrent duplications may shed light on the pathophysiology of esotropia.

}, keywords = {Case-Control Studies, DNA Copy Number Variations, Esotropia, Female, Gene Duplication, Gene Frequency, Genetic Predisposition to Disease, Genotyping Techniques, Humans, Infant, Male, Markov Chains, Polymerase Chain Reaction, Risk Factors}, issn = {1552-5783}, doi = {10.1167/iovs.61.10.22}, author = {Whitman, Mary C and Di Gioia, Silvio Alessandro and Chan, Wai-Man and Gelber, Alon and Pratt, Brandon M and Bell, Jessica L and Collins, Thomas E and Knowles, James A and Armoskus, Christopher and Pato, Michele and Pato, Carlos and Shaaban, Sherin and Staffieri, Sandra and MacKinnon, Sarah and Maconachie, Gail D E and Elder, James E and Traboulsi, Elias I and Gottlob, Irene and Mackey, David A and Hunter, David G and Engle, Elizabeth C} } @article {755, title = {Severe neurodevelopmental disease caused by a homozygous TLK2 variant.}, journal = {Eur J Hum Genet}, volume = {28}, year = {2020}, month = {2020 03}, pages = {383-387}, abstract = {

A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

}, keywords = {Adult, Cerebellum, Child, Developmental Disabilities, Female, Heterozygote, Homozygote, Humans, Infant, Male, Mutation, Missense, Nervous System Malformations, Pedigree, Protein Kinases, Spasms, Infantile}, issn = {1476-5438}, doi = {10.1038/s41431-019-0519-x}, author = {Topf, Ana and Oktay, Yavuz and Balaraju, Sunitha and Yilmaz, Elmasnur and Sonmezler, Ece and Yis, Uluc and Laurie, Steven and Thompson, Rachel and Roos, Andreas and MacArthur, Daniel G and Yaramis, Ahmet and G{\"u}ng{\"o}r, Serdal and Lochm{\"u}ller, Hanns and Hiz, Semra and Horvath, Rita} } @article {966, title = {Successful treatment of intractable epilepsy with ketogenic diet therapy in twins with ALG3-CDG.}, journal = {Brain Dev}, volume = {42}, year = {2020}, month = {2020 Aug}, pages = {539-545}, abstract = {

BACKGROUND: Congenital disorders of glycosylation (CDG) is a heterogeneous group of congenital metabolic diseases with multisystem clinical involvement. ALG3-CDG is a very rare subtype with only 24 cases reported so far.

CASE: Here, we report two siblings with dysmorphic features, growth retardation, microcephaly, intractable epilepsy, and hemangioma in the frontal, occipital and lumbosacral regions.

RESULTS: We studied two siblings by whole exome sequencing. A pathogenic variant in ALG3 (NM_005787.6: c.165C~>~T; p.Gly55=) that had been previously associated with congenital glycolysis defect type 1d was identified. Their intractable seizures were controlled by ketogenic diet.

CONCLUSION: Although prominent findings of growth retardation and microcephaly seen in our patients have been extensively reported before, presence of hemangioma is a novel finding that may be used as an indication for ALG3-CDG diagnosis. Our patients are the first reported cases whose intractable seizures were controlled with ketogenic diet. This report adds ketogenic diet as an option for treatment of intractable epilepsy in ALG3-CDG.

}, keywords = {Central Nervous System Neoplasms, Congenital Disorders of Glycosylation, Craniofacial Abnormalities, Developmental Disabilities, Diet, Ketogenic, Drug Resistant Epilepsy, Female, Hemangioma, Humans, Infant, Male, Mannosyltransferases, Twins, Whole Exome Sequencing}, issn = {1872-7131}, doi = {10.1016/j.braindev.2020.04.008}, author = {Paketci, C and Edem, P and Hiz, S and Sonmezler, E and Soydemir, D and Sarikaya Uzan, G and Oktay, Y and O{\textquoteright}Heir, E and Beltran, S and Laurie, S and T{\"o}pf, A and Lochmuller, H and Horvath, R and Yis, U} } @article {580, title = {De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome.}, journal = {Genome Med}, volume = {11}, year = {2019}, month = {2019 02 28}, pages = {12}, abstract = {

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity).

METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes.

RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances.

CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.

}, keywords = {Adolescent, Child, Child, Preschool, Craniofacial Abnormalities, Developmental Disabilities, Female, Humans, INDEL Mutation, Infant, Intellectual Disability, Male, Muscle Hypotonia, Smith-Magenis Syndrome, Transcription Factors, Young Adult}, issn = {1756-994X}, doi = {10.1186/s13073-019-0623-0}, author = {Vetrini, Francesco and McKee, Shane and Rosenfeld, Jill A and Suri, Mohnish and Lewis, Andrea M and Nugent, Kimberly Margaret and Roeder, Elizabeth and Littlejohn, Rebecca O and Holder, Sue and Zhu, Wenmiao and Alaimo, Joseph T and Graham, Brett and Harris, Jill M and Gibson, James B and Pastore, Matthew and McBride, Kim L and Komara, Makanko and Al-Gazali, Lihadh and Al Shamsi, Aisha and Fanning, Elizabeth A and Wierenga, Klaas J and Scott, Daryl A and Ben-Neriah, Ziva and Meiner, Vardiella and Cassuto, Hanoch and Elpeleg, Orly and Holder, J Lloyd and Burrage, Lindsay C and Seaver, Laurie H and Van Maldergem, Lionel and Mahida, Sonal and Soul, Janet S and Marlatt, Margaret and Matyakhina, Ludmila and Vogt, Julie and Gold, June-Anne and Park, Soo-Mi and Varghese, Vinod and Lampe, Anne K and Kumar, Ajith and Lees, Melissa and Holder-Espinasse, Muriel and McConnell, Vivienne and Bernhard, Birgitta and Blair, Ed and Harrison, Victoria and Muzny, Donna M and Gibbs, Richard A and Elsea, Sarah H and Posey, Jennifer E and Bi, Weimin and Lalani, Seema and Xia, Fan and Yang, Yaping and Eng, Christine M and Lupski, James R and Liu, Pengfei} } @article {656, title = {Exploring by whole exome sequencing patients with initial diagnosis of Rubinstein-Taybi syndrome: the interconnections of epigenetic machinery disorders.}, journal = {Hum Genet}, volume = {138}, year = {2019}, month = {2019 Mar}, pages = {257-269}, abstract = {

Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disease affecting 1:125,000 newborns characterized by intellectual disability, growth retardation, facial dysmorphisms and skeletal abnormalities. RSTS is caused by mutations in genes encoding for writers of the epigenetic machinery: CREBBP (~ 60\%) or its homologous EP300 (~ 10\%). No causative mutation is identified in up to 30\% of patients. We performed whole-exome sequencing (WES) on eight RSTS-like individuals who had normal high-resolution array CGH testing and were CREBBP- and EP300-mutation -negative, to identify the molecular cause. In four cases, we identified putatively causal variants in three genes (ASXL1, KMT2D and KMT2A) encoding members of the epigenetic machinery known to be associated with the Bohring-Opitz, Kabuki and Wiedemann-Steiner syndromes. Each variant is novel, de novo, fulfills the ACMG criteria and is predicted to result in loss-of-function leading to haploinsufficiency of the epi-gene. In two of the remaining cases, homozygous/compound heterozygous variants in XYLT2 and PLCB4 genes, respectively, associated with spondyloocular and auriculocondylar 2 syndromes and in the latter an additional candidate variant in XRN2, a gene yet unrelated to any disease, were detected, but their pathogenicity remains uncertain. These results underscore the broad clinical spectrum of Mendelian disorders of the epigenetic apparatus and the high rate of WES disclosure of the genetic basis in cases which may pose a challenge for phenotype encompassing distinct syndromes. The overlapping features of distinct intellectual disability syndromes reflect common pathogenic molecular mechanisms affecting the complex regulation of balance between open and closed chromatin.

}, keywords = {Child, Child, Preschool, Comparative Genomic Hybridization, CREB-Binding Protein, E1A-Associated p300 Protein, Epigenesis, Genetic, Facies, Female, Genetic Association Studies, Humans, Infant, Infant, Newborn, Male, Mutation, Phenotype, Rubinstein-Taybi Syndrome, Whole Exome Sequencing}, issn = {1432-1203}, doi = {10.1007/s00439-019-01985-y}, author = {Negri, Gloria and Magini, Pamela and Milani, Donatella and Crippa, Milena and Biamino, Elisa and Piccione, Maria and Sotgiu, Stefano and Perr{\`\i}a, Chiara and Vitiello, Giuseppina and Frontali, Marina and Boni, Antonella and Di Fede, Elisabetta and Gandini, Maria Chiara and Colombo, Elisa Adele and Bamshad, Michael J and Nickerson, Deborah A and Smith, Joshua D and Loddo, Italia and Finelli, Palma and Seri, Marco and Pippucci, Tommaso and Larizza, Lidia and Gervasini, Cristina} } @article {561, title = {Novel SPEG mutations in congenital myopathies: Genotype-phenotype correlations.}, journal = {Muscle Nerve}, volume = {59}, year = {2019}, month = {2019 03}, pages = {357-362}, abstract = {

INTRODUCTION: Centronuclear myopathies (CNMs) are a subtype of congenital myopathies (CMs) characterized by muscle weakness, predominant type 1 fibers, and increased central nuclei. SPEG (striated preferentially expressed protein kinase) mutations have recently been identified in 7 CM patients (6 with CNMs). We report 2 additional patients with SPEG mutations expanding the phenotype and evaluate genotype-phenotype correlations associated with SPEG mutations.

METHODS: Using whole exome/genome sequencing in CM families, we identified novel recessive SPEG mutations in 2 patients.

RESULTS: Patient 1, with severe muscle weakness requiring respiratory support, dilated cardiomyopathy, ophthalmoplegia, and findings of nonspecific CM on muscle biopsy carried a homozygous SPEG mutation (p.Val3062del). Patient 2, with milder muscle weakness, ophthalmoplegia, and CNM carried compound heterozygous mutations (p.Leu728Argfs*82) and (p.Val2997Glyfs*52).

CONCLUSIONS: The 2 patients add insight into genotype-phenotype correlations of SPEG-associated CMs. Clinicians should consider evaluating a CM patient for SPEG mutations even in the absence of CNM features. Muscle Nerve 59:357-362, 2019.

}, keywords = {Biopsy, Child, Child, Preschool, Consanguinity, Exome, Female, Genetic Association Studies, Humans, Infant, Male, Muscle Proteins, Muscle Weakness, Muscle, Skeletal, Mutation, Myopathies, Structural, Congenital, Protein-Serine-Threonine Kinases, Sequence Analysis}, issn = {1097-4598}, doi = {10.1002/mus.26378}, author = {Qualls, Anita E and Donkervoort, Sandra and Herkert, Johanna C and D{\textquoteright}Gama, Alissa M and Bharucha-Goebel, Diana and Collins, James and Chao, Katherine R and Foley, A Reghan and Schoots, Mirthe H and Jongbloed, Jan D H and B{\"o}nnemann, Carsten G and Agrawal, Pankaj B} } @article {570, title = {TBX6 compound inheritance leads to congenital vertebral malformations in humans and mice.}, journal = {Hum Mol Genet}, volume = {28}, year = {2019}, month = {2019 02 15}, pages = {539-547}, abstract = {

Congenital vertebral malformations (CVMs) are associated with human TBX6 compound inheritance that combines a rare null allele and a common hypomorphic allele at the TBX6 locus. Our previous in vitro evidence suggested that this compound inheritance resulted in a TBX6 gene dosage of less than haploinsufficiency (i.e. <50\%) as a potential mechanism of TBX6-associated CVMs. To further investigate this pathogenetic model, we ascertained and collected 108 Chinese CVM cases and found that 10 (9.3\%) of them carried TBX6 null mutations in combination with common hypomorphic variants at the second TBX6 allele. For in vivo functional verification and genetic analysis of TBX6 compound inheritance, we generated both null and hypomorphic mutations in mouse Tbx6 using the CRISPR-Cas9 method. These Tbx6 mutants are not identical to the patient variants at the DNA sequence level, but instead functionally mimic disease-associated TBX6 variants. Intriguingly, as anticipated by the compound inheritance model, a high penetrance of CVM phenotype was only observed in the mice with combined null and hypomorphic alleles of Tbx6. These findings are consistent with our experimental observations in humans and supported the dosage effect of TBX6 in CVM etiology. In conclusion, our findings in the newly collected human CVM subjects and Tbx6 mouse models consistently support the contention that TBX6 compound inheritance causes CVMs, potentially via a gene dosage-dependent mechanism. Furthermore, mouse Tbx6 mutants mimicking human CVM-associated variants will be useful models for further mechanistic investigations of CVM pathogenesis in the cases associated with TBX6.

}, keywords = {Adolescent, Alleles, Animals, Child, Child, Preschool, Congenital Abnormalities, CRISPR-Cas Systems, Disease Models, Animal, Female, Haploinsufficiency, Humans, Infant, Male, Mice, Mutation, Phenotype, Scoliosis, Spine, T-Box Domain Proteins}, issn = {1460-2083}, doi = {10.1093/hmg/ddy358}, author = {Yang, Nan and Wu, Nan and Zhang, Ling and Zhao, Yanxue and Liu, Jiaqi and Liang, Xiangyu and Ren, Xiaojun and Li, Weiyu and Chen, Weisheng and Dong, Shuangshuang and Zhao, Sen and Lin, Jiachen and Xiang, Hang and Xue, Huadan and Chen, Lu and Sun, Hao and Zhang, Jianguo and Shi, Jiangang and Zhang, Shuyang and Lu, Daru and Wu, Xiaohui and Jin, Li and Ding, Jiandong and Qiu, Guixing and Wu, Zhihong and Lupski, James R and Zhang, Feng} } @article {577, title = {ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {319-330}, abstract = {

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de~novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In~vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In~vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.

}, keywords = {Alleles, Animals, Child, Child, Preschool, Developmental Disabilities, Female, Humans, Infant, Intellectual Disability, Male, Mice, Point Mutation, Syndrome, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.007}, author = {Carapito, Raphael and Ivanova, Ekaterina L and Morlon, Aurore and Meng, Linyan and Molitor, Anne and Erdmann, Eva and Kieffer, Bruno and Pichot, Ang{\'e}lique and Naegely, Lydie and Kolmer, Aline and Paul, Nicod{\`e}me and Hanauer, Antoine and Tran Mau-Them, Fr{\'e}d{\'e}ric and Jean-Mar{\c c}ais, Nolwenn and Hiatt, Susan M and Cooper, Gregory M and Tvrdik, Tatiana and Muir, Alison M and Dimartino, Cl{\'e}mantine and Chopra, Maya and Amiel, Jeanne and Gordon, Christopher T and Dutreux, Fabien and Garde, Aurore and Thauvin-Robinet, Christel and Wang, Xia and Leduc, Magalie S and Phillips, Meredith and Crawford, Heather P and Kukolich, Mary K and Hunt, David and Harrison, Victoria and Kharbanda, Mira and Smigiel, Robert and Gold, Nina and Hung, Christina Y and Viskochil, David H and Dugan, Sarah L and Bayrak-Toydemir, Pinar and Joly-Helas, G{\'e}raldine and Guerrot, Anne-Marie and Schluth-Bolard, Caroline and Rio, Marl{\`e}ne and Wentzensen, Ingrid M and McWalter, Kirsty and Schnur, Rhonda E and Lewis, Andrea M and Lalani, Seema R and Mensah-Bonsu, No{\"e}l and C{\'e}raline, Jocelyn and Sun, Zijie and Ploski, Rafal and Bacino, Carlos A and Mefford, Heather C and Faivre, Laurence and Bodamer, Olaf and Chelly, Jamel and Isidor, Bertrand and Bahram, Seiamak} } @article {436, title = {Additional features of Gillespie syndrome in two Brazilian siblings with a novel ITPR1 homozygous pathogenic variant.}, journal = {Eur J Med Genet}, volume = {61}, year = {2018}, month = {2018 Mar}, pages = {134-138}, abstract = {

Gillespie syndrome (GS) [MIM: 206700] is a very rare condition characterized by bilateral iris defect, congenital hypotonia, cerebellar ataxia and intellectual disability. The typical iris anomaly is considered necessary to the diagnosis of GS. Recently, variants in ITPR1 were described causing GS. Non-neurological features were reported in few patients. Here we describe two consanguineous siblings with GS and a novel homozygous ITPR1 pathogenic variant (p.N984fs). They also present a cardiac defect (pulmonary valve stenosis) and one sib had a genitourinary malformation (ureteropelvic junction obstruction). Our report reinforces ITPR1 as the cause of GS and suggests a possible role of ITPR1 in the development of other organs.

}, keywords = {Aniridia, Brazil, Cerebellar Ataxia, Child, Preschool, Consanguinity, Female, Homozygote, Humans, Infant, Inositol 1,4,5-Trisphosphate Receptors, Intellectual Disability, Male, Mutation, Pedigree, Siblings}, issn = {1878-0849}, doi = {10.1016/j.ejmg.2017.11.005}, author = {Carvalho, Daniel R and Medeiros, Jo{\~a}o Eugenio G and Ribeiro, Daniela Sebestyan M and Martins, Bernardo J A F and Sobreira, Nara L M} } @article {548, title = {Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Dec}, pages = {921-939}, abstract = {

Juvenile segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ starting in childhood. Hutchinson-Gilford progeria syndrome (HGPS), caused by a recurrent de novo synonymous LMNA mutation resulting in aberrant splicing and generation of a mutant product called progerin, is a prototypical example of such disorders. Here, we performed a joint collaborative study using massively parallel sequencing and targeted Sanger sequencing, aimed at delineating the underlying genetic cause of 14 previously undiagnosed, clinically heterogeneous, non-LMNA-associated juvenile progeroid patients. The molecular diagnosis was achieved in 11 of 14 cases (~ 79\%). Furthermore, we firmly establish biallelic mutations in POLR3A as the genetic cause of a recognizable, neonatal, Wiedemann-Rautenstrauch-like progeroid syndrome. Thus, we suggest that POLR3A mutations are causal for a portion of under-diagnosed early-onset segmental progeroid syndromes. We additionally expand the clinical spectrum associated with PYCR1 mutations by showing that they can somewhat resemble HGPS in the first year of life. Moreover, our results lead to clinical reclassification in one single case. Our data emphasize the complex genetic and clinical heterogeneity underlying progeroid disorders.

}, keywords = {Adolescent, Alternative Splicing, Child, Female, Fetal Growth Retardation, Genetic Predisposition to Disease, Humans, Infant, Lamin Type A, Male, Mutation, Phenotype, Progeria, Pyrroline Carboxylate Reductases, RNA Polymerase III}, issn = {1432-1203}, doi = {10.1007/s00439-018-1957-1}, author = {Lessel, Davor and Ozel, Ayse Bilge and Campbell, Susan E and Saadi, Abdelkrim and Arlt, Martin F and McSweeney, Keisha Melodi and Plaiasu, Vasilica and Szakszon, Katalin and Sz{\H o}ll{\H o}s, Anna and Rusu, Cristina and Rojas, Armando J and Lopez-Valdez, Jaime and Thiele, Holger and N{\"u}rnberg, Peter and Nickerson, Deborah A and Bamshad, Michael J and Li, Jun Z and Kubisch, Christian and Glover, Thomas W and Gordon, Leslie B} } @article {504, title = {CARD14-associated papulosquamous eruption: A spectrum including features of psoriasis and pityriasis rubra pilaris.}, journal = {J Am Acad Dermatol}, volume = {79}, year = {2018}, month = {2018 Sep}, pages = {487-494}, abstract = {

BACKGROUND: Heterozygous mutations in caspase recruitment domain family member 14 gene (CARD14) have been shown to be associated with psoriasis and familial pityriasis rubra pilaris (PRP). Many subjects with CARD14 mutations display features of both disorders, which can result in diagnostic uncertainty. In addition, these eruptions are often recalcitrant to conventional psoriasis therapies such as methotrexate, oral retinoids, and tumor necrosis factor-α inhibitors.

OBJECTIVE: We sought to describe the clinical characteristics, family history, and response to therapy in subjects with papulosquamous eruptions due to mutations in CARD14.

METHODS: Subjects were referred for genetic testing as part of a registry of subjects with inherited disorders of keratinization. DNA was isolated from blood or saliva, and multiplex targeted sequencing or whole exome sequencing was performed. Clinical histories of subjects with CARD14 mutations were reviewed.

RESULTS: We identified 15 kindreds with CARD14-associated papulosquamous eruption (CAPE). Characteristic features of CAPE include early age of onset; prominent involvement of the cheeks, chin, and ears; family history of psoriasis or PRP; minimal response to conventional topical and systemic psoriasis therapies; and improvement with ustekinumab.

LIMITATIONS: Relatively small sample size.

CONCLUSIONS: Many subjects with CARD14 mutations display characteristics of both psoriasis and PRP. We propose the term CARD14-associated papulosquamous eruption to describe this spectrum of disease. Subjects with clinical features suggestive of CAPE should undergo CARD14 sequencing and may benefit from treatment with ustekinumab.

}, keywords = {Age of Onset, CARD Signaling Adaptor Proteins, Child, Child, Preschool, Dermatologic Agents, Facial Dermatoses, Genetic Testing, Guanylate Cyclase, Humans, Infant, Infant, Newborn, Membrane Proteins, Phenotype, Pityriasis Rubra Pilaris, Psoriasis, Retreatment, Skin Diseases, Papulosquamous, Ustekinumab}, issn = {1097-6787}, doi = {10.1016/j.jaad.2018.02.034}, author = {Craiglow, Brittany G and Boyden, Lynn M and Hu, Ronghua and Virtanen, Marie and Su, John and Rodriguez, Gabriela and McCarthy, Catherine and Luna, Paula and Larralde, Margarita and Humphrey, Stephen and Holland, Kristen E and Hogeling, Marcia and Hidalgo-Matlock, Benjamin and Ferrari, Bruno and Fernandez-Faith, Esteban and Drolet, Beth and Cordoro, Kelly M and Bowcock, Anne M and Antaya, Richard J and Ashack, Kurt and Ashack, Richard J and Lifton, Richard P and Milstone, Leonard M and Paller, Amy S and Choate, Keith A} } @article {541, title = {Discordance in the Dependence on Kisspeptin Signaling in Mini Puberty vs Adolescent Puberty: Human Genetic Evidence.}, journal = {J Clin Endocrinol Metab}, volume = {103}, year = {2018}, month = {2018 04 01}, pages = {1273-1276}, abstract = {

Context: Hypothalamic kisspeptin signaling plays a critical role in the initiation and maintenance of reproductive function. Biallelic mutations in the coding sequence of KISS1R (GPR54) have been identified in patients with idiopathic hypogonadotropic hypogonadism, but it is unknown whether biallelic variants can also be associated with related reproductive disorders.

Case Description: A missense homozygous variant (c.890G>T p.R297L) in KISS1R was identified in a child who presented with microphallus and bilateral cryptorchidism. This variant has been reported to reduce, but not abolish, postreceptor signaling in vitro. Biochemical evaluation during the neonatal period revealed low testosterone levels. By 11 years and 8 months, the boy began demonstrating increases in testicular volume. By 17 years and 3 months, his testicular volume was 20 mL; his penile length was 7.3 cm; and he had adult levels of circulating gonadotropins and testosterone.

Conclusion: This case report associates biallelic loss-of-function mutations in KISS1R with normal timing of adolescent puberty. Because these coding sequence variants occurred in a patient with microphallus and cryptorchidism, they demonstrate different levels of dependence of the hypothalamic-pituitary-gonadal cascade on kisspeptin signaling at distinct times in the reproductive life span. The suppression of the hypothalamic-pituitary-gonadal cascade during early life but not adolescence suggests that the mini puberty of infancy depends more on kisspeptin-induced, gonadotropin-releasing hormone-induced luteinizing hormone secretion than does adolescent puberty.

}, keywords = {Cryptorchidism, Follicle Stimulating Hormone, Follow-Up Studies, Humans, Infant, Kisspeptins, Luteinizing Hormone, Male, Mutation, Missense, Penis, Receptors, Kisspeptin-1, Sexual Maturation, Signal Transduction, Testosterone}, issn = {1945-7197}, doi = {10.1210/jc.2017-02636}, author = {Shahab, Muhammad and Lippincott, Margaret and Chan, Yee-Ming and Davies, Addie and Merino, Paulina M and Plummer, Lacey and Mericq, Veronica and Seminara, Stephanie} } @article {435, title = {FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.}, journal = {Pediatr Diabetes}, volume = {19}, year = {2018}, month = {2018 05}, pages = {388-392}, abstract = {

Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause "immune dysregulation, polyendocrinopathy (including insulin-requiring diabetes), enteropathy, X-linked" (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole-exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT-PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice-site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT-PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early-onset insulin-requiring diabetes with or without other features of IPEX syndrome.

}, keywords = {Diabetes Mellitus, Diabetes Mellitus, Type 1, Diarrhea, Forkhead Transcription Factors, Genetic Diseases, X-Linked, Humans, Immune System Diseases, Infant, Infant, Newborn, Male, Registries}, issn = {1399-5448}, doi = {10.1111/pedi.12612}, author = {Hwang, Jessica L and Park, Soo-Young and Ye, Honggang and Sanyoura, May and Pastore, Ashley N and Carmody, David and Del Gaudio, Daniela and Wilson, Janna F and Hanis, Craig L and Liu, Xiaoming and Atzmon, Gil and Glaser, Benjamin and Philipson, Louis H and Greeley, Siri Atma W} } @article {431, title = {Genetic analysis of CHARGE syndrome identifies overlapping molecular biology.}, journal = {Genet Med}, volume = {20}, year = {2018}, month = {2018 09}, pages = {1022-1029}, abstract = {

PURPOSE: CHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7, encoding adenosine triphosphate-dependent chromodomain helicase DNA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5-30\% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome.

METHODS: We performed whole-exome sequencing (WES) on 28 families from which at least one individual presented with features highly suggestive of CHARGE syndrome.

RESULTS: Pathogenic variants in CHD7 were present in 15 of 28 individuals (53.6\%), whereas 4 (14.3\%) individuals had pathogenic variants in other genes (RERE, KMT2D, EP300, or PUF60). A variant of uncertain clinical significance in KDM6A was identified in one (3.5\%) individual. The remaining eight (28.6\%) individuals were not found to have pathogenic variants by WES.

CONCLUSION: These results demonstrate that the phenotypic features of CHARGE syndrome overlap with multiple other rare single-gene syndromes. Additionally, they implicate a shared molecular pathology that disrupts epigenetic regulation of multiple-organ development.

}, keywords = {Adolescent, Adult, Carrier Proteins, CHARGE Syndrome, Child, Child, Preschool, Cohort Studies, DNA Helicases, DNA-Binding Proteins, E1A-Associated p300 Protein, Epigenesis, Genetic, Female, Genetic Testing, Humans, Infant, Male, Mutation, Neoplasm Proteins, Phenotype, Repressor Proteins, RNA Splicing Factors}, issn = {1530-0366}, doi = {10.1038/gim.2017.233}, author = {Moccia, Amanda and Srivastava, Anshika and Skidmore, Jennifer M and Bernat, John A and Wheeler, Marsha and Chong, Jessica X and Nickerson, Deborah and Bamshad, Michael and Hefner, Margaret A and Martin, Donna M and Bielas, Stephanie L} } @article {500, title = {Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {753-768}, abstract = {

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant~located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.

}, keywords = {Adolescent, Adult, Carrier Proteins, Channelopathies, Child, Child, Preschool, Developmental Disabilities, Female, Genetic Markers, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Phenotype, Sodium Channels, Young Adult}, issn = {1432-1203}, doi = {10.1007/s00439-018-1929-5}, author = {Bramswig, Nuria C and Bertoli-Avella, Aida M and Albrecht, Beate and Al Aqeel, Aida I and Alhashem, Amal and Al-Sannaa, Nouriya and Bah, Maissa and Br{\"o}hl, Katharina and Depienne, Christel and Dorison, Nathalie and Doummar, Diane and Ehmke, Nadja and Elbendary, Hasnaa M and Gorokhova, Svetlana and H{\'e}ron, Delphine and Horn, Denise and James, Kiely and Keren, Boris and Kuechler, Alma and Ismail, Samira and Issa, Mahmoud Y and Marey, Isabelle and Mayer, Mich{\`e}le and McEvoy-Venneri, Jennifer and Megarbane, Andre and Mignot, Cyril and Mohamed, Sarar and Nava, Caroline and Philip, Nicole and Ravix, Cecile and Rolfs, Arndt and Sadek, Abdelrahim Abdrabou and Segebrecht, Lara and Stanley, Valentina and Trautman, Camille and Valence, Stephanie and Villard, Laurent and Wieland, Thomas and Engels, Hartmut and Strom, Tim M and Zaki, Maha S and Gleeson, Joseph G and L{\"u}decke, Hermann-Josef and Bauer, Peter and Wieczorek, Dagmar} } @article {474, title = {Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 06 07}, pages = {1143-1157}, abstract = {

Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. Herein, pathogenic variants are described in four genes encoding components of the p120-catenin complex (CTNND1, PLEKHA7, PLEKHA5) and an epithelial splicing regulator (ESRP2), in addition to the known CL/P-associated gene, CDH1, which encodes E-cadherin. The findings were also validated in a second cohort of 497 people with NS-CL/P, comprising small families and singletons with pathogenic variants in these genes identified in 14\% of multi-affected families and 2\% of the replication cohort of smaller families. Enriched expression of each gene/protein in human and mouse embryonic oro-palatal epithelia, demonstration of functional impact of CTNND1 and ESRP2 variants, and recapitulation of the CL/P spectrum in Ctnnd1 knockout mice support a causative role in CL/P pathogenesis. These data show that primary defects in regulators of epithelial cell adhesion are the most significant contributors to NS-CL/P identified to date and that inherited and de novo single gene variants explain a substantial proportion of NS-CL/P.

}, keywords = {Alleles, Amino Acid Sequence, Animals, Biotinylation, Cadherins, Catenins, Cleft Lip, Cleft Palate, Epithelium, Female, Gene Deletion, Genetic Predisposition to Disease, Humans, Infant, Infant, Newborn, Male, Mice, Mutation, Palate, Pedigree, Syndrome, Whole Exome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.04.009}, author = {Cox, Liza L and Cox, Timothy C and Moreno Uribe, Lina M and Zhu, Ying and Richter, Chika T and Nidey, Nichole and Standley, Jennifer M and Deng, Mei and Blue, Elizabeth and Chong, Jessica X and Yang, Yueqin and Carstens, Russ P and Anand, Deepti and Lachke, Salil A and Smith, Joshua D and Dorschner, Michael O and Bedell, Bruce and Kirk, Edwin and Hing, Anne V and Venselaar, Hanka and Valencia-Ramirez, Luz C and Bamshad, Michael J and Glass, Ian A and Cooper, Jonathan A and Haan, Eric and Nickerson, Deborah A and van Bokhoven, Hans and Zhou, Huiqing and Krahn, Katy N and Buckley, Michael F and Murray, Jeffrey C and Lidral, Andrew C and Roscioli, Tony} } @article {432, title = {Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive~TNNT3~splice variant.}, journal = {Hum Mutat}, volume = {39}, year = {2018}, month = {2018 03}, pages = {383-388}, abstract = {

A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibers with striking nemaline rods and hypertrophy of slow fibers that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in TNNT3 (chr11:1956150G~>~A, NM_006757.3:c.681+1G~>~A). TNNT3 encodes skeletal troponin-T and is associated with autosomal dominant distal arthrogryposis. TNNT3 has not previously been associated with nemaline myopathy (NM), a rare congenital myopathy linked to defects in proteins associated with thin filament structure and regulation. cDNA studies confirmed pathogenic consequences of the splice variant, eliciting exon-skipping and intron retention events leading to a frameshift. Western blot showed deficiency of troponin-T protein with secondary loss of troponin-I . We establish a homozygous splice variant in TNNT3 as the likely cause of severe congenital NM with distal arthrogryposis, characterized by specific involvement of Type-2 fibers and deficiency of troponin-T .

}, keywords = {Arthrogryposis, Genes, Recessive, Humans, Infant, Infant, Newborn, Male, Myopathies, Nemaline, RNA Splice Sites, RNA Splicing, RNA, Messenger, Troponin T}, issn = {1098-1004}, doi = {10.1002/humu.23385}, author = {Sandaradura, Sarah A and Bournazos, Adam and Mallawaarachchi, Amali and Cummings, Beryl B and Waddell, Leigh B and Jones, Kristi J and Troedson, Christopher and Sudarsanam, Annapurna and Nash, Benjamin M and Peters, Gregory B and Algar, Elizabeth M and MacArthur, Daniel G and North, Kathryn N and Brammah, Susan and Charlton, Amanda and Laing, Nigel G and Wilson, Meredith J and Davis, Mark R and Cooper, Sandra T} } @article {613, title = {A novel NAA10 variant with impaired acetyltransferase activity causes developmental delay, intellectual disability, and hypertrophic cardiomyopathy.}, journal = {Eur J Hum Genet}, volume = {26}, year = {2018}, month = {2018 09}, pages = {1294-1305}, abstract = {

The NAA10-NAA15 complex (NatA) is an N-terminal acetyltransferase that catalyzes N-terminal acetylation of ~40\% of all human proteins. N-terminal acetylation has several different roles in the cell, including altering protein stability and degradation, protein localization and protein-protein interactions. In recent years several X-linked NAA10 variants have been associated with genetic disorders. We have identified a previously undescribed NAA10 c.215T>C p.(Ile72Thr) variant in three boys from two unrelated families with a milder phenotypic spectrum in comparison to most of the previously described patients with NAA10 variants. These boys have development delay, intellectual disability, and cardiac abnormalities as overlapping phenotypes. Functional studies reveal that NAA10 Ile72Thr is destabilized, while binding to NAA15 most likely is intact. Surprisingly, the NatA activity of NAA10 Ile72Thr appears normal while its monomeric activity is decreased. This study further broadens the phenotypic spectrum associated with NAA10 deficiency, and adds to the evidence that genotype-phenotype correlations for NAA10 variants are much more complex than initially anticipated.

}, keywords = {Cardiomyopathy, Hypertrophic, Child, Preschool, Developmental Disabilities, Enzyme Stability, HeLa Cells, Humans, Infant, Intellectual Disability, Male, Mutation, N-Terminal Acetyltransferase A, N-Terminal Acetyltransferase E, Phenotype, Protein Binding, Syndrome}, issn = {1476-5438}, doi = {10.1038/s41431-018-0136-0}, author = {St{\o}ve, Svein Isungset and Blenski, Marina and Stray-Pedersen, Asbj{\o}rg and Wierenga, Klaas J and Jhangiani, Shalini N and Akdemir, Zeynep Coban and Crawford, David and McTiernan, Nina and Myklebust, Line M and Purcarin, Gabriela and McNall-Knapp, Rene and Wadley, Alexandrea and Belmont, John W and Kim, Jeffrey J and Lupski, James R and Arnesen, Thomas} } @article {629, title = {A novel pathogenic variant in a family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {4}, year = {2018}, month = {2018 02}, abstract = {

Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent attacks of dyskinetic movements without alteration of consciousness that are often triggered by the initiation of voluntary movements. Whole-exome sequencing has revealed a cluster of pathogenic variants in (proline-rich transmembrane protein), a gene with a function in synaptic regulation that remains poorly understood. Here, we report the discovery of a novel pathogenic variant inherited in an autosomal dominant pattern in a family with PKD and benign familial infantile seizures (BFIS). After targeted Sanger sequencing did not identify the presence of previously described pathogenic variants, we carried out whole-exome sequencing in the proband and her affected paternal grandfather. This led to the discovery of a novel variant, NM_001256442:exon3:c.C959T/NP_660282.2:p.A320V, altering an evolutionarily conserved alanine at the amino acid position 320 located in the M2 transmembrane region. Sanger sequencing further confirmed the presence of this variant in four affected family members (paternal grandfather, father, brother, and proband) and its absence in two unaffected ones (paternal grandmother and mother). This newly found variant further reinforces the importance of in PKD, BFIS, and possibly other movement disorders. Future functional studies using animal models and human pluripotent stem cell models will provide new insights into the role of and the significance of this variant in regulating neural development and/or function.

}, keywords = {Amino Acid Sequence, Base Sequence, Child, Chromosome Segregation, Conserved Sequence, Dystonia, Epilepsy, Benign Neonatal, Evolution, Molecular, Family, Female, Humans, Infant, Inheritance Patterns, Male, Membrane Proteins, Mutation, Nerve Tissue Proteins, Pedigree}, issn = {2373-2873}, doi = {10.1101/mcs.a002287}, author = {Lu, Jacqueline G and Bishop, Juliet and Cheyette, Sarah and Zhulin, Igor B and Guo, Su and Sobreira, Nara and Brenner, Steven E} } @article {465, title = {The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia.}, journal = {Hum Mol Genet}, volume = {27}, year = {2018}, month = {2018 06 15}, pages = {2064-2075}, abstract = {

Congenital diaphragmatic hernia (CDH) has been reported twice in individuals with a clinical diagnosis of Fraser syndrome, a genetic disorder that can be caused by recessive mutations affecting FREM2 and FRAS1. In the extracellular matrix, FREM2 and FRAS1 form a self-stabilizing complex with FREM1, a protein whose deficiency causes sac CDH in humans and mice. By sequencing FREM2 and FRAS1 in a CDH cohort, and searching online databases, we identified five individuals who carried recessive or double heterozygous, putatively deleterious variants in these genes which may represent susceptibility alleles. Three of these alleles were significantly enriched in our CDH cohort compared with ethnically matched controls. We subsequently demonstrated that 8\% of Frem2ne/ne and 1\% of Fras1Q1263*/Q1263* mice develop the same type of anterior sac CDH seen in FREM1-deficient mice. We went on to show that development of sac hernias in FREM1-deficient mice is preceded by failure of anterior mesothelial fold progression resulting in the persistence of an amuscular, poorly vascularized anterior diaphragm that is abnormally adherent to the underlying liver. Herniation occurs in the perinatal period when the expanding liver protrudes through this amuscular region of the anterior diaphragm that is juxtaposed to areas of muscular diaphragm. Based on these data, we conclude that deficiency of FREM2, and possibly FRAS1, are associated with an increased risk of developing CDH and that loss of the FREM1/FREM2/FRAS1 complex, or its function, leads to anterior sac CDH development through its effects on mesothelial fold progression.

}, keywords = {Animals, Child, Child, Preschool, Epithelium, Extracellular Matrix Proteins, Female, Hernias, Diaphragmatic, Congenital, Humans, Infant, Infant, Newborn, Male, Mice, Mice, Knockout, Mutation, Pregnancy, Receptors, Interleukin}, issn = {1460-2083}, doi = {10.1093/hmg/ddy110}, author = {Jordan, Valerie K and Beck, Tyler F and Hernandez-Garcia, Andres and Kundert, Peter N and Kim, Bum-Jun and Jhangiani, Shalini N and Gambin, Tomasz and Starkovich, Molly and Punetha, Jaya and Paine, Ingrid S and Posey, Jennifer E and Li, Alexander H and Muzny, Donna and Hsu, Chih-Wei and Lashua, Amber J and Sun, Xin and Fernandes, Caraciolo J and Dickinson, Mary E and Lally, Kevin P and Gibbs, Richard A and Boerwinkle, Eric and Lupski, James R and Scott, Daryl A} } @article {490, title = {Variants in EXOSC9 Disrupt the RNA Exosome and Result in Cerebellar Atrophy with Spinal Motor Neuronopathy.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 05 03}, pages = {858-873}, abstract = {

The exosome is a conserved multi-protein complex that is essential for correct RNA processing. Recessive variants in exosome components EXOSC3, EXOSC8, and RBM7 cause various constellations of pontocerebellar hypoplasia (PCH), spinal muscular atrophy (SMA), and central nervous system demyelination. Here, we report on four unrelated affected individuals with recessive variants in EXOSC9 and the effect of the variants on the function of the RNA exosome in~vitro in affected individuals{\textquoteright} fibroblasts and skeletal muscle and in~vivo in zebrafish. The clinical presentation was severe, early-onset, progressive SMA-like motor neuronopathy, cerebellar atrophy, and in one affected individual, congenital fractures of the long bones. Three affected individuals of different ethnicity carried the homozygous c.41T>C (p.Leu14Pro) variant, whereas one affected individual was compound heterozygous for c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161). We detected reduced EXOSC9 in fibroblasts and skeletal muscle and observed a reduction of the whole multi-subunit exosome complex on blue-native polyacrylamide gel electrophoresis. RNA sequencing of fibroblasts and skeletal muscle detected significant >2-fold changes in genes involved in neuronal development and cerebellar and motor neuron degeneration, demonstrating the widespread effect of the variants. Morpholino oligonucleotide knockdown and CRISPR/Cas9-mediated mutagenesis of exosc9 in zebrafish recapitulated aspects of the human phenotype, as they have in other zebrafish models of exosomal disease. Specifically, portions of the cerebellum and hindbrain were absent, and motor neurons failed to develop and migrate properly. In summary, we show that variants in EXOSC9 result in a neurological syndrome combining cerebellar atrophy and spinal motoneuronopathy, thus expanding the list of human exosomopathies.

}, keywords = {Amino Acid Sequence, Animals, Atrophy, Base Sequence, Cerebellum, Child, Preschool, Exosome Multienzyme Ribonuclease Complex, Exosomes, Female, Fibroblasts, Gene Knockdown Techniques, Genetic Variation, Haplotypes, Humans, Infant, Male, Motor Neurons, Muscle, Skeletal, Pedigree, RNA-Binding Proteins, Spinal Cord, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.03.011}, author = {Burns, David T and Donkervoort, Sandra and M{\"u}ller, Juliane S and Knierim, Ellen and Bharucha-Goebel, Diana and Faqeih, Eissa Ali and Bell, Stephanie K and AlFaifi, Abdullah Y and Monies, Dorota and Millan, Francisca and Retterer, Kyle and Dyack, Sarah and MacKay, Sara and Morales-Gonzalez, Susanne and Giunta, Michele and Munro, Benjamin and Hudson, Gavin and Scavina, Mena and Baker, Laura and Massini, Tara C and Lek, Monkol and Hu, Ying and Ezzo, Daniel and Alkuraya, Fowzan S and Kang, Peter B and Griffin, Helen and Foley, A Reghan and Schuelke, Markus and Horvath, Rita and B{\"o}nnemann, Carsten G} } @article {441, title = {Whole exome sequencing frequently detects a monogenic cause in early onset nephrolithiasis and~nephrocalcinosis.}, journal = {Kidney Int}, volume = {93}, year = {2018}, month = {2018 01}, pages = {204-213}, abstract = {

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4\% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8\% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

}, keywords = {Adolescent, Age of Onset, Child, Child, Preschool, Disease Progression, Female, Genetic Association Studies, Genetic Markers, Genetic Predisposition to Disease, Heredity, Humans, Infant, Male, Mutation, Nephrocalcinosis, Nephrolithiasis, Pedigree, Phenotype, Predictive Value of Tests, Prognosis, Risk Factors, Tomography, X-Ray Computed, Ultrasonography, Whole Exome Sequencing, Young Adult}, issn = {1523-1755}, doi = {10.1016/j.kint.2017.06.025}, author = {Daga, Ankana and Majmundar, Amar J and Braun, Daniela A and Gee, Heon Yung and Lawson, Jennifer A and Shril, Shirlee and Jobst-Schwan, Tilman and Vivante, Asaf and Schapiro, David and Tan, Weizhen and Warejko, Jillian K and Widmeier, Eugen and Nelson, Caleb P and Fathy, Hanan M and Gucev, Zoran and Soliman, Neveen A and Hashmi, Seema and Halbritter, Jan and Halty, Margarita and Kari, Jameela A and El-Desoky, Sherif and Ferguson, Michael A and Somers, Michael J G and Traum, Avram Z and Stein, Deborah R and Daouk, Ghaleb H and Rodig, Nancy M and Katz, Avi and Hanna, Christian and Schwaderer, Andrew L and Sayer, John A and Wassner, Ari J and Mane, Shrikant and Lifton, Richard P and Milosevic, Danko and Tasic, Velibor and Baum, Michelle A and Hildebrandt, Friedhelm} } @article {371, title = {Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency.}, journal = {Mitochondrion}, volume = {34}, year = {2017}, month = {2017 05}, pages = {84-90}, abstract = {

We report the clinical, biochemical, and molecular findings in two brothers with encephalopathy and multi-systemic disease. Abnormal transferrin glycoforms were suggestive of a type I congenital disorder of glycosylation (CDG). While exome sequencing was negative for CDG related candidate genes, the testing revealed compound heterozygous mutations in the mitochondrial elongation factor G gene (GFM1). One of the mutations had been reported previously while the second, novel variant was found deep in intron 6, activating a cryptic splice site. Functional studies demonstrated decreased GFM1 protein levels, suggested disrupted assembly of mitochondrial complexes III and V and decreased activities of mitochondrial complexes I and IV, all indicating combined OXPHOS deficiency.

}, keywords = {Child, Child, Preschool, Congenital Abnormalities, Gene Expression, Humans, Infant, Infant, Newborn, Male, Mitochondrial Proteins, Oxidative Phosphorylation, Peptide Elongation Factor G, RNA Splice Sites}, issn = {1872-8278}, doi = {10.1016/j.mito.2017.02.004}, author = {Simon, Mariella T and Ng, Bobby G and Friederich, Marisa W and Wang, Raymond Y and Boyer, Monica and Kircher, Martin and Collard, Renata and Buckingham, Kati J and Chang, Richard and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J and Van Hove, Johan L K and Freeze, Hudson H and Abdenur, Jose E} } @article {449, title = {Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO.}, journal = {J Med Genet}, volume = {54}, year = {2017}, month = {2017 01}, pages = {47-53}, abstract = {

BACKGROUND: The non-POU domain containing octamer-binding gene (NONO) is located on chromosome Xq13.1 and encodes a member of a small family of RNA-binding and DNA-binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Loss-of-function variants in NONO have been described as a cause of intellectual disability in males but have not been described in association with congenital heart defects or cardiomyopathy. In this article, we seek to further define the phenotypic consequences of NONO depletion in human subjects.

METHODS: We searched a clinical database of over 6000 individuals referred for exome sequencing and over 60 000 individuals referred for CNV analysis.

RESULTS: We identified two males with atrial and ventricular septal defects, left ventricular non-compaction (LVNC), developmental delay and intellectual disability, who harboured de novo, loss-of-function variants in NONO. We also identified a male infant with developmental delay, congenital brain anomalies and severe LVNC requiring cardiac transplantation, who inherited a single-gene deletion of NONO from his asymptomatic mother.

CONCLUSIONS: We conclude that in addition to global developmental delay and intellectual disability, males with loss-of-function variants in NONO may also be predisposed to developing congenital heart defects and LVNC with the penetrance of these cardiac-related problems being influenced by genetic, epigenetic, environmental or stochastic factors. Brain imaging of males with NONO deficiency may reveal structural defects with abnormalities of the corpus callosum being the most common. Although dysmorphic features vary between affected individuals, relative macrocephaly is a common feature.

}, keywords = {Child, Child, Preschool, Developmental Disabilities, DNA-Binding Proteins, Exome, Heart Defects, Congenital, Heart Ventricles, Humans, Infant, Male, Nuclear Matrix-Associated Proteins, Octamer Transcription Factors, RNA-Binding Proteins}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-104039}, author = {Scott, Daryl A and Hernandez-Garcia, Andres and Azamian, Mahshid S and Jordan, Valerie K and Kim, Bum Jun and Starkovich, Molly and Zhang, Jinglan and Wong, Lee-Jun and Darilek, Sandra A and Breman, Amy M and Yang, Yaping and Lupski, James R and Jiwani, Amyn K and Das, Bibhuti and Lalani, Seema R and Iglesias, Alejandro D and Rosenfeld, Jill A and Xia, Fan} } @article {353, title = {Corner fracture type spondylometaphyseal dysplasia: Overlap with type II collagenopathies.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Mar}, pages = {733-739}, abstract = {

Spondylometaphyseal dysplasia (SMD) corner fracture type (also known as SMD "Sutcliffe" type, MIM 184255) is a rare skeletal dysplasia that presents with mild to moderate short stature, developmental coxa vara, mild platyspondyly, corner fracture-like lesions, and metaphyseal abnormalities with sparing of the epiphyses. The molecular basis for this disorder has yet to be clarified. We describe two patients with SMD corner fracture type and heterozygous pathogenic variants in COL2A1. These two cases together with a third case of SMD corner fracture type with a heterozygous COL2A1 pathogenic variant previously described suggest that this disorder overlaps with type II collagenopathies. The finding of one of the pathogenic variants in a previously reported case of spondyloepimetaphyseal dysplasia (SEMD) Strudwick type and the significant clinical similarity suggest an overlap between SMD corner fracture and SEMD Strudwick types. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Alleles, Amino Acid Substitution, Bone Diseases, Developmental, Child, Preschool, Collagen Type II, Diagnosis, Differential, Exome, Genetic Association Studies, Genotype, Growth Disorders, High-Throughput Nucleotide Sequencing, Hip Joint, Humans, Infant, Male, Mutation, Osteochondrodysplasias, Phenotype, Radiography, Tibial Fractures}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38059}, author = {Machol, Keren and Jain, Mahim and Almannai, Mohammed and Orand, Thibault and Lu, James T and Tran, Alyssa and Chen, Yuqing and Schlesinger, Alan and Gibbs, Richard and Bonafe, Luisa and Campos-Xavier, Ana Belinda and Unger, Sheila and Superti-Furga, Andrea and Lee, Brendan H and Campeau, Philippe M and Burrage, Lindsay C} } @article {335, title = {De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Feb 02}, pages = {352-363}, abstract = {

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

}, keywords = {Adolescent, Animals, Child, Child, Preschool, Disease Models, Animal, DNA Copy Number Variations, Down-Regulation, Female, Gene Deletion, Humans, Infant, Intellectual Disability, Male, Microcephaly, Neurodevelopmental Disorders, Polymorphism, Single Nucleotide, Proteasome Endopeptidase Complex, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.01.003}, author = {K{\"u}ry, S{\'e}bastien and Besnard, Thomas and Ebstein, Fr{\'e}d{\'e}ric and Khan, Tahir N and Gambin, Tomasz and Douglas, Jessica and Bacino, Carlos A and Craigen, William J and Sanders, Stephan J and Lehmann, Andrea and Latypova, X{\'e}nia and Khan, Kamal and Pacault, Mathilde and Sacharow, Stephanie and Glaser, Kimberly and Bieth, Eric and Perrin-Sabourin, Laurence and Jacquemont, Marie-Line and Cho, Megan T and Roeder, Elizabeth and Denomm{\'e}-Pichon, Anne-Sophie and Monaghan, Kristin G and Yuan, Bo and Xia, Fan and Simon, Sylvain and Bonneau, Dominique and Parent, Philippe and Gilbert-Dussardier, Brigitte and Odent, Sylvie and Toutain, Annick and Pasquier, Laurent and Barbouth, Deborah and Shaw, Chad A and Patel, Ankita and Smith, Janice L and Bi, Weimin and Schmitt, S{\'e}bastien and Deb, Wallid and Nizon, Mathilde and Mercier, Sandra and Vincent, Marie and Rooryck, Caroline and Malan, Val{\'e}rie and Brice{\~n}o, Ignacio and G{\'o}mez, Alberto and Nugent, Kimberly M and Gibson, James B and Cogn{\'e}, Benjamin and Lupski, James R and Stessman, Holly A F and Eichler, Evan E and Retterer, Kyle and Yang, Yaping and Redon, Richard and Katsanis, Nicholas and Rosenfeld, Jill A and Kloetzel, Peter-Michael and Golzio, Christelle and B{\'e}zieau, St{\'e}phane and Stankiewicz, Pawe{\l} and Isidor, Bertrand} } @article {633, title = {De novo mutations in HNRNPU result in a neurodevelopmental syndrome.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Nov}, pages = {3003-3012}, abstract = {

Exome sequencing in the context of developmental disorders is a useful technique, but variants found need to be interpreted in the context of detailed phenotypic information. Whole gene deletions and loss-of-function-mutations in the HNRNPU gene have been associated with intellectual disability and seizures in some patients. However, a unifying syndromic phenotype has not been previously elucidated. Here, we report a total of seven patients (six patients identified through the Wellcome Trust Deciphering Developmental Disorders study, with one additional patient), who have heterozygous de novo mutations in HNRNPU. These were found via trio-based exome sequencing. All but one of the mutations is predicted to cause loss-of-function. These patients have dysmorphic features in common, including prominent eyebrows, long palpebral fissures, overhanging columella, and thin upper lip. All patients have developmental delay and intellectual disability (ID), ranging from moderate to severe. Seizures are common from early childhood. These initially occur in the context of febrile episodes. This series demonstrates common phenotypic features, including emerging dysmorphism, associated with heterozygous HNRNPU mutations. This allows us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Developmental Disabilities, Exome, Female, Genetic Predisposition to Disease, Haploinsufficiency, Heterogeneous-Nuclear Ribonucleoprotein U, Heterozygote, Humans, Infant, Intellectual Disability, Male, Mutation, Neurodevelopmental Disorders, Phenotype, Seizures, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38492}, author = {Yates, T Michael and Vasudevan, Pradeep C and Chandler, Kate E and Donnelly, Deirdre E and Stark, Zornitza and Sadedin, Simon and Willoughby, Josh and Balasubramanian, Meena} } @article {638, title = {A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome.}, journal = {Nat Commun}, volume = {8}, year = {2017}, month = {2017 07 06}, pages = {16077}, abstract = {

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymk zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.

}, keywords = {Adult, Amino Acid Sequence, Animals, Cell Fusion, Child, Disease Models, Animal, Embryo, Nonmammalian, Female, Gene Expression, Genes, Recessive, Genetic Complementation Test, Humans, Infant, Male, Membrane Proteins, Mobius Syndrome, Morphogenesis, Muscle Proteins, Muscle, Skeletal, Muscular Diseases, Mutation, Myoblasts, Pedigree, Pierre Robin Syndrome, Sequence Alignment, Sequence Homology, Amino Acid, Zebrafish, Zebrafish Proteins}, issn = {2041-1723}, doi = {10.1038/ncomms16077}, author = {Di Gioia, Silvio Alessandro and Connors, Samantha and Matsunami, Norisada and Cannavino, Jessica and Rose, Matthew F and Gilette, Nicole M and Artoni, Pietro and de Macena Sobreira, Nara Lygia and Chan, Wai-Man and Webb, Bryn D and Robson, Caroline D and Cheng, Long and Van Ryzin, Carol and Ramirez-Martinez, Andres and Mohassel, Payam and Leppert, Mark and Scholand, Mary Beth and Grunseich, Christopher and Ferreira, Carlos R and Hartman, Tyler and Hayes, Ian M and Morgan, Tim and Markie, David M and Fagiolini, Michela and Swift, Amy and Chines, Peter S and Speck-Martins, Carlos E and Collins, Francis S and Jabs, Ethylin Wang and B{\"o}nnemann, Carsten G and Olson, Eric N and Carey, John C and Robertson, Stephen P and Manoli, Irini and Engle, Elizabeth C} } @article {365, title = {Diagnosis of Chronic Intestinal Pseudo-obstruction and Megacystis by Sequencing the ACTG2 Gene.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {65}, year = {2017}, month = {2017 10}, pages = {384-387}, abstract = {

OBJECTIVES: The diagnosis of chronic intestinal pseudo-obstruction has depended on clinical features, manometry, and imaging. This report aimed to determine the efficacy of sequencing the actin γ-2 (ACTG2) gene for diagnosis. In addition, the goal was to determine how often a mutation would be found in our randomly collected cohort of probands and those probands published previously.

METHODS: Whole exome sequencing was performed in 4 probands with chronic intestinal pseudo-obstruction. Subsequently, only the ACTG2 gene was sequenced in another 24 probands (total 28). We analyzed published data of 83 probands and our 28 (total 111) and determined how many had pathogenic variants and the precise genotype.

RESULTS: Whole exome and Sanger sequencing revealed a pathogenic variant in the ACTG2 gene in 4 out of 28 of our probands and in 45 out of 83 published probands (49/111 [44.1\%]). Moreover, a mutational hotspot in the ACTG2 gene was recognized. Genetic heterogeneity is evident.

CONCLUSIONS: Pooled gene sequencing results from 1 individual in each of 111 families enabled a precise diagnosis of an ACTG2 mutation in 49 (44\%). The benefit to patients and families of early confirmation of a motility disorder not only helps avoid unnecessary intervention, but also enables institution of appropriate treatments and avoidance of secondary disorders such as malnutrition and poor growth. Knowledge of a pathogenic variant in a parent, with a 50\% risk of recurrence, provides an opportunity for genetic counseling.

}, keywords = {Actins, Adult, Child, Child, Preschool, Chronic Disease, Duodenum, Female, Fetal Diseases, Genetic Markers, Genetic Testing, Humans, Infant, Infant, Newborn, Intestinal Pseudo-Obstruction, Male, Mutation, Sequence Analysis, DNA, Urinary Bladder, Whole Exome Sequencing}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000001608}, author = {Milunsky, Aubrey and Baldwin, Clinton and Zhang, Xiaoying and Primack, Daniel and Curnow, Adrian and Milunsky, Jeff} } @article {57, title = {Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2.}, journal = {Genet Med}, volume = {19}, year = {2017}, month = {2017 01}, pages = {13-19}, abstract = {

PURPOSE: Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by de novo mutations in MECP2 and sometimes in CDKL5 and FOXG1. However, some RTT patients lack mutations in these genes.

METHODS: Twenty-two RTT patients without apparent MECP2, CDKL5, and FOXG1 mutations were subjected to both whole-exome sequencing and single-nucleotide polymorphism array-based copy-number variant (CNV) analyses.

RESULTS: Three patients had MECP2 mutations initially missed by clinical testing. Of the remaining 19, 17 (89.5\%) had 29 other likely pathogenic intragenic mutations and/or CNVs (10 patients had 2 or more). Interestingly, 13 patients had mutations in a gene/region previously reported in other neurodevelopmental disorders (NDDs), thereby providing a potential diagnostic yield of 68.4\%. These mutations were significantly enriched in chromatin regulators (corrected P = 0.0068) and moderately enriched in postsynaptic cell membrane molecules (corrected P = 0.076), implicating glutamate receptor signaling.

CONCLUSION: The genetic etiology of RTT without MECP2, CDKL5, and FOXG1 mutations is heterogeneous, overlaps with other NDDs, and complicated by a high mutation burden. Dysregulation of chromatin structure and abnormal excitatory synaptic signaling may form two common pathological bases of RTT.Genet Med 19 1, 13-19.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chromatin, DNA Copy Number Variations, Female, Forkhead Transcription Factors, Humans, Infant, Male, Methyl-CpG-Binding Protein 2, Mutation, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Protein-Serine-Threonine Kinases, Rett Syndrome, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/gim.2016.42}, author = {Sajan, Samin A and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Lupski, James R and Glaze, Daniel G and Kaufmann, Walter E and Skinner, Steven A and Annese, Fran and Friez, Michael J and Lane, Jane and Percy, Alan K and Neul, Jeffrey L} } @article {368, title = {An exome sequencing study of Moebius syndrome including atypical cases reveals an individual with CFEOM3A and a mutation.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {3}, year = {2017}, month = {2017 03}, pages = {a000984}, abstract = {

Moebius syndrome is characterized by congenital unilateral or bilateral facial and abducens nerve palsies (sixth and seventh cranial nerves) causing facial weakness, feeding difficulties, and restricted ocular movements. Abnormalities of the chest wall such as Poland anomaly and variable limb defects are frequently associated with this syndrome. Most cases are isolated; however, rare families with autosomal dominant transmission with incomplete penetrance and variable expressivity have been described. The genetic basis of this condition remains unknown. In a cohort study of nine individuals suspected to have Moebius syndrome (six typical, three atypical), we performed whole-exome sequencing to try to identify a commonly mutated gene. Although no such gene was identified and we did not find mutations in and , we found a de novo heterozygous mutation, p.E410K, in the gene encoding tubulin beta 3 class III (), in an individual with atypical Moebius syndrome. This individual was diagnosed with near-complete ophthalmoplegia, agenesis of the corpus callosum, and absence of the septum pellucidum. No substantial limb abnormalities were noted. Mutations in have been associated with complex cortical dysplasia and other brain malformations and congenital fibrosis of extraocular muscles type 3A (CFEOM3A). Our report highlights the overlap of genetic etiology and clinical differences between CFEOM and Moebius syndrome and describes our approach to identifying candidate genes for typical and atypical Moebius syndrome.

}, keywords = {Child, Child, Preschool, Cohort Studies, Exome, Eye Diseases, Hereditary, Facial Paralysis, Female, Humans, Infant, Male, Malformations of Cortical Development, Mobius Syndrome, Muscular Diseases, Mutation, Ocular Motility Disorders, Ophthalmoplegia, Orbital Diseases, Pedigree, Tubulin, Whole Exome Sequencing}, issn = {2373-2873}, doi = {10.1101/mcs.a000984}, author = {Patel, Ronak M and Liu, David and Gonzaga-Jauregui, Claudia and Jhangiani, Shalini and Lu, James T and Sutton, V Reid and Fernbach, Susan D and Azamian, Mahshid and White, Lisa and Edmond, Jane C and Paysse, Evelyn A and Belmont, John W and Muzny, Donna and Lupski, James R and Gibbs, Richard A and Lewis, Richard Alan and Lee, Brendan H and Lalani, Seema R and Campeau, Philippe M} } @article {350, title = {Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.}, journal = {N Engl J Med}, volume = {376}, year = {2017}, month = {2017 02 23}, pages = {742-754}, abstract = {

BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.

METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice.

RESULTS: We identified heterozygous deletions of 22q11.2 in 1.1\% of the patients with congenital kidney anomalies and in 0.01\% of population controls (odds ratio, 81.5; P=4.5{\texttimes}10). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies.

CONCLUSIONS: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Animals, Child, Chromosome Deletion, Chromosomes, Human, Pair 22, DiGeorge Syndrome, Exome, Female, Haploinsufficiency, Heterozygote, Humans, Infant, Infant, Newborn, Kidney, Male, Mice, Models, Animal, Nuclear Proteins, Sequence Analysis, DNA, Urinary Tract, Young Adult, Zebrafish}, issn = {1533-4406}, doi = {10.1056/NEJMoa1609009}, author = {Lopez-Rivera, Esther and Liu, Yangfan P and Verbitsky, Miguel and Anderson, Blair R and Capone, Valentina P and Otto, Edgar A and Yan, Zhonghai and Mitrotti, Adele and Martino, Jeremiah and Steers, Nicholas J and Fasel, David A and Vukojevic, Katarina and Deng, Rong and Racedo, Silvia E and Liu, Qingxue and Werth, Max and Westland, Rik and Vivante, Asaf and Makar, Gabriel S and Bodria, Monica and Sampson, Matthew G and Gillies, Christopher E and Vega-Warner, Virginia and Maiorana, Mariarosa and Petrey, Donald S and Honig, Barry and Lozanovski, Vladimir J and Salomon, R{\'e}mi and Heidet, Laurence and Carpentier, Wassila and Gaillard, Dominique and Carrea, Alba and Gesualdo, Loreto and Cusi, Daniele and Izzi, Claudia and Scolari, Francesco and van Wijk, Joanna A E and Arapovic, Adela and Saraga-Babic, Mirna and Saraga, Marijan and Kunac, Nenad and Samii, Ali and McDonald-McGinn, Donna M and Crowley, Terrence B and Zackai, Elaine H and Drozdz, Dorota and Miklaszewska, Monika and Tkaczyk, Marcin and Sikora, Przemyslaw and Szczepanska, Maria and Mizerska-Wasiak, Malgorzata and Krzemien, Grazyna and Szmigielska, Agnieszka and Zaniew, Marcin and Darlow, John M and Puri, Prem and Barton, David and Casolari, Emilio and Furth, Susan L and Warady, Bradley A and Gucev, Zoran and Hakonarson, Hakon and Flogelova, Hana and Tasic, Velibor and Latos-Bielenska, Anna and Materna-Kiryluk, Anna and Allegri, Landino and Wong, Craig S and Drummond, Iain A and D{\textquoteright}Agati, Vivette and Imamoto, Akira and Barasch, Jonathan M and Hildebrandt, Friedhelm and Kiryluk, Krzysztof and Lifton, Richard P and Morrow, Bernice E and Jeanpierre, Cecile and Papaioannou, Virginia E and Ghiggeri, Gian Marco and Gharavi, Ali G and Katsanis, Nicholas and Sanna-Cherchi, Simone} } @article {369, title = {Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features.}, journal = {Hum Genet}, volume = {136}, year = {2017}, month = {2017 04}, pages = {377-386}, abstract = {

Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin-proteasome dependent disorders.

}, keywords = {Adolescent, Autism Spectrum Disorder, Carrier Proteins, Child, Child, Preschool, Cohort Studies, DNA Copy Number Variations, Facies, Female, Haploinsufficiency, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Ubiquitin-Protein Ligases}, issn = {1432-1203}, doi = {10.1007/s00439-017-1763-1}, author = {Zhang, Jing and Gambin, Tomasz and Yuan, Bo and Szafranski, Przemyslaw and Rosenfeld, Jill A and Balwi, Mohammed Al and Alswaid, Abdulrahman and Al-Gazali, Lihadh and Shamsi, Aisha M Al and Komara, Makanko and Ali, Bassam R and Roeder, Elizabeth and McAuley, Laura and Roy, Daniel S and Manchester, David K and Magoulas, Pilar and King, Lauren E and Hannig, Vickie and Bonneau, Dominique and Denomm{\'e}-Pichon, Anne-Sophie and Charif, Majida and Besnard, Thomas and B{\'e}zieau, St{\'e}phane and Cogn{\'e}, Benjamin and Andrieux, Joris and Zhu, Wenmiao and He, Weimin and Vetrini, Francesco and Ward, Patricia A and Cheung, Sau Wai and Bi, Weimin and Eng, Christine M and Lupski, James R and Yang, Yaping and Patel, Ankita and Lalani, Seema R and Xia, Fan and Stankiewicz, Pawe{\l}} } @article {442, title = {Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders.}, journal = {Genome Med}, volume = {9}, year = {2017}, month = {2017 08 14}, pages = {73}, abstract = {

BACKGROUND: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder.

METHODS: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review.

RESULTS: We demonstrate greater than expected phenotypic heterogeneity, including 33\% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites.

CONCLUSIONS: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified.

}, keywords = {Adolescent, Adult, CDC2 Protein Kinase, Child, Child, Preschool, Face, Female, Heart Defects, Congenital, Humans, Infant, Intellectual Disability, Male, Mutation, Phenotype, Syndrome}, issn = {1756-994X}, doi = {10.1186/s13073-017-0463-8}, author = {Bostwick, Bret L and McLean, Scott and Posey, Jennifer E and Streff, Haley E and Gripp, Karen W and Blesson, Alyssa and Powell-Hamilton, Nina and Tusi, Jessica and Stevenson, David A and Farrelly, Ellyn and Hudgins, Louanne and Yang, Yaping and Xia, Fan and Wang, Xia and Liu, Pengfei and Walkiewicz, Magdalena and McGuire, Marianne and Grange, Dorothy K and Andrews, Marisa V and Hummel, Marybeth and Madan-Khetarpal, Suneeta and Infante, Elena and Coban-Akdemir, Zeynep and Miszalski-Jamka, Karol and Jefferies, John L and Rosenfeld, Jill A and Emrick, Lisa and Nugent, Kimberly M and Lupski, James R and Belmont, John W and Lee, Brendan and Lalani, Seema R} } @article {399, title = {Phenotypic spectrum of autosomal recessive congenital ichthyosis due to PNPLA1 mutation.}, journal = {Br J Dermatol}, volume = {177}, year = {2017}, month = {2017 07}, pages = {319-322}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Heterozygote, Homozygote, Humans, Ichthyosis, Infant, Lipase, Male, Middle Aged, Mutation, Missense, Pedigree, Phenotype, Young Adult}, issn = {1365-2133}, doi = {10.1111/bjd.15570}, author = {Boyden, L M and Craiglow, B G and Hu, R H and Zhou, J and Browning, J and Eichenfield, L and Lim, Y L and Luu, M and Randolph, L M and Ginarte, M and Fachal, L and Rodriguez-Pazos, L and Vega, A and Kramer, D and Yosipovitch, G and Vahidnezhad, H and Youssefian, L and Uitto, J and Lifton, R P and Paller, A S and Milstone, L M and Choate, K A} } @article {27, title = {Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.}, journal = {J Allergy Clin Immunol}, volume = {139}, year = {2017}, month = {2017 Jan}, pages = {232-245}, abstract = {

BACKGROUND: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions.

OBJECTIVE: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs.

METHODS: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping.

RESULTS: A likely molecular diagnosis was achieved in 110 (40\%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30~Kb that would not have been detected with conventional diagnostic CNV arrays.

CONCLUSION: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

}, keywords = {Adolescent, Adult, Aged, Child, Child, Preschool, DNA Copy Number Variations, Female, Genomics, High-Throughput Nucleotide Sequencing, Humans, Immunologic Deficiency Syndromes, Infant, Male, Middle Aged, Young Adult}, issn = {1097-6825}, doi = {10.1016/j.jaci.2016.05.042}, author = {Stray-Pedersen, Asbj{\o}rg and Sorte, Hanne S{\o}rmo and Samarakoon, Pubudu and Gambin, Tomasz and Chinn, Ivan K and Coban Akdemir, Zeynep H and Erichsen, Hans Christian and Forbes, Lisa R and Gu, Shen and Yuan, Bo and Jhangiani, Shalini N and Muzny, Donna M and R{\o}dningen, Olaug Kristin and Sheng, Ying and Nicholas, Sarah K and Noroski, Lenora M and Seeborg, Filiz O and Davis, Carla M and Canter, Debra L and Mace, Emily M and Vece, Timothy J and Allen, Carl E and Abhyankar, Harshal A and Boone, Philip M and Beck, Christine R and Wiszniewski, Wojciech and Fevang, B{\o}rre and Aukrust, P{\r a}l and Tj{\o}nnfjord, Geir E and Gedde-Dahl, Tobias and Hjorth-Hansen, Henrik and Dybedal, Ingunn and Nord{\o}y, Ingvild and J{\o}rgensen, Silje F and Abrahamsen, Tore G and {\O}verland, Torstein and Bechensteen, Anne Grete and Skogen, Vegard and Osnes, Liv T N and Kulseth, Mari Ann and Prescott, Trine E and Rustad, Cecilie F and Heimdal, Ketil R and Belmont, John W and Rider, Nicholas L and Chinen, Javier and Cao, Tram N and Smith, Eric A and Caldirola, Maria Soledad and Bezrodnik, Liliana and Lugo Reyes, Saul Oswaldo and Espinosa Rosales, Francisco J and Guerrero-Cursaru, Nina Denisse and Pedroza, Luis Alberto and Poli, Cecilia M and Franco, Jose L and Trujillo Vargas, Claudia M and Aldave Becerra, Juan Carlos and Wright, Nicola and Issekutz, Thomas B and Issekutz, Andrew C and Abbott, Jordan and Caldwell, Jason W and Bayer, Diana K and Chan, Alice Y and Aiuti, Alessandro and Cancrini, Caterina and Holmberg, Eva and West, Christina and Burstedt, Magnus and Karaca, Ender and Yesil, G{\"o}zde and Artac, Hasibe and Bayram, Yavuz and Atik, Mehmed Musa and Eldomery, Mohammad K and Ehlayel, Mohammad S and Jolles, Stephen and Flat{\o}, Berit and Bertuch, Alison A and Hanson, I Celine and Zhang, Victor W and Wong, Lee-Jun and Hu, Jianhong and Walkiewicz, Magdalena and Yang, Yaping and Eng, Christine M and Boerwinkle, Eric and Gibbs, Richard A and Shearer, William T and Lyle, Robert and Orange, Jordan S and Lupski, James R} } @article {355, title = {PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment.}, journal = {Brain}, volume = {140}, year = {2017}, month = {2017 Apr 01}, pages = {940-952}, abstract = {

PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.

}, keywords = {Adolescent, Brain, Carrier Proteins, Cell Differentiation, Cell Movement, Cerebral Cortex, Child, Child, Preschool, Cytoskeleton, Developmental Disabilities, Female, Genes, Recessive, Heredodegenerative Disorders, Nervous System, Humans, Infant, Male, Microcephaly, Microtubules, Mutation, Pedigree, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awx014}, author = {Zollo, Massimo and Ahmed, Mustafa and Ferrucci, Veronica and Salpietro, Vincenzo and Asadzadeh, Fatemeh and Carotenuto, Marianeve and Maroofian, Reza and Al-Amri, Ahmed and Singh, Royana and Scognamiglio, Iolanda and Mojarrad, Majid and Musella, Luca and Duilio, Angela and Di Somma, Angela and Karaca, Ender and Rajab, Anna and Al-Khayat, Aisha and Mohan Mohapatra, Tribhuvan and Eslahi, Atieh and Ashrafzadeh, Farah and Rawlins, Lettie E and Prasad, Rajniti and Gupta, Rashmi and Kumari, Preeti and Srivastava, Mona and Cozzolino, Flora and Kumar Rai, Sunil and Monti, Maria and Harlalka, Gaurav V and Simpson, Michael A and Rich, Philip and Al-Salmi, Fatema and Patton, Michael A and Chioza, Barry A and Efthymiou, Stephanie and Granata, Francesca and Di Rosa, Gabriella and Wiethoff, Sarah and Borgione, Eugenia and Scuderi, Carmela and Mankad, Kshitij and Hanna, Michael G and Pucci, Piero and Houlden, Henry and Lupski, James R and Crosby, Andrew H and Baple, Emma L} } @article {334, title = {A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Feb 02}, pages = {343-351}, abstract = {

Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who~underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p~= 1.25~{\texttimes} 10). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1.

}, keywords = {Alleles, Amino Acid Sequence, Brain, Cataract, Child, Child, Preschool, Female, Genetic Variation, Genome-Wide Association Study, Humans, Infant, Intellectual Disability, Magnetic Resonance Imaging, Male, Microcephaly, Mutation, Missense, Neoplasm Proteins, Pedigree, Phenotype, Repressor Proteins, Spasms, Infantile}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.12.013}, author = {Schoch, Kelly and Meng, Linyan and Szelinger, Szabolcs and Bearden, David R and Stray-Pedersen, Asbjorg and Busk, Oyvind L and Stong, Nicholas and Liston, Eriskay and Cohn, Ronald D and Scaglia, Fernando and Rosenfeld, Jill A and Tarpinian, Jennifer and Skraban, Cara M and Deardorff, Matthew A and Friedman, Jeremy N and Akdemir, Zeynep Coban and Walley, Nicole and Mikati, Mohamad A and Kranz, Peter G and Jasien, Joan and McConkie-Rosell, Allyn and McDonald, Marie and Wechsler, Stephanie Burns and Freemark, Michael and Kansagra, Sujay and Freedman, Sharon and Bali, Deeksha and Millan, Francisca and Bale, Sherri and Nelson, Stanley F and Lee, Hane and Dorrani, Naghmeh and Goldstein, David B and Xiao, Rui and Yang, Yaping and Posey, Jennifer E and Martinez-Agosto, Julian A and Lupski, James R and Wangler, Michael F and Shashi, Vandana} } @article {406, title = {SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Feb}, pages = {238-248}, abstract = {

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84\% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

}, keywords = {Adolescent, Child, Child, Preschool, Choanal Atresia, Chromosomal Proteins, Non-Histone, Female, Genetic Predisposition to Disease, Humans, Infant, Male, Microphthalmos, Muscular Dystrophies, Mutation, Nose, Phenotype}, issn = {1546-1718}, doi = {10.1038/ng.3743}, author = {Shaw, Natalie D and Brand, Harrison and Kupchinsky, Zachary A and Bengani, Hemant and Plummer, Lacey and Jones, Takako I and Erdin, Serkan and Williamson, Kathleen A and Rainger, Joe and Stortchevoi, Alexei and Samocha, Kaitlin and Currall, Benjamin B and Dunican, Donncha S and Collins, Ryan L and Willer, Jason R and Lek, Angela and Lek, Monkol and Nassan, Malik and Pereira, Shahrin and Kammin, Tammy and Lucente, Diane and Silva, Alexandra and Seabra, Catarina M and Chiang, Colby and An, Yu and Ansari, Morad and Rainger, Jacqueline K and Joss, Shelagh and Smith, Jill Clayton and Lippincott, Margaret F and Singh, Sylvia S and Patel, Nirav and Jing, Jenny W and Law, Jennifer R and Ferraro, Nalton and Verloes, Alain and Rauch, Anita and Steindl, Katharina and Zweier, Markus and Scheer, Ianina and Sato, Daisuke and Okamoto, Nobuhiko and Jacobsen, Christina and Tryggestad, Jeanie and Chernausek, Steven and Schimmenti, Lisa A and Brasseur, Benjamin and Cesaretti, Claudia and Garc{\'\i}a-Ortiz, Jose E and Buitrago, Tatiana Pineda and Silva, Orlando Perez and Hoffman, Jodi D and M{\"u}hlbauer, Wolfgang and Ruprecht, Klaus W and Loeys, Bart L and Shino, Masato and Kaindl, Angela M and Cho, Chie-Hee and Morton, Cynthia C and Meehan, Richard R and van Heyningen, Veronica and Liao, Eric C and Balasubramanian, Ravikumar and Hall, Janet E and Seminara, Stephanie B and Macarthur, Daniel and Moore, Steven A and Yoshiura, Koh-Ichiro and Gusella, James F and Marsh, Joseph A and Graham, John M and Lin, Angela E and Katsanis, Nicholas and Jones, Peter L and Crowley, William F and Davis, Erica E and FitzPatrick, David R and Talkowski, Michael E} } @article {540, title = {Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management.}, journal = {JAMA Pediatr}, volume = {171}, year = {2017}, month = {2017 12 04}, pages = {e173438}, abstract = {

Importance: While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined.

Objective: To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants.

Design, Setting, and Participants: Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children{\textquoteright}s Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants.

Main Outcomes and Measures: Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders.

Results: The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7\%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0\%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8\%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9\%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1\%) by exome sequencing, with implications for recurrence risk counseling.

Conclusions and Relevance: Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.

}, keywords = {Adult, Critical Care, Disease Management, Exome, Genetic Counseling, Genetic Diseases, Inborn, Humans, Infant, Infant Care, Infant, Newborn, Intensive Care Units, Pediatric, Length of Stay, Retrospective Studies, Texas, Whole Exome Sequencing}, issn = {2168-6211}, doi = {10.1001/jamapediatrics.2017.3438}, author = {Meng, Linyan and Pammi, Mohan and Saronwala, Anirudh and Magoulas, Pilar and Ghazi, Andrew Ray and Vetrini, Francesco and Zhang, Jing and He, Weimin and Dharmadhikari, Avinash V and Qu, Chunjing and Ward, Patricia and Braxton, Alicia and Narayanan, Swetha and Ge, Xiaoyan and Tokita, Mari J and Santiago-Sim, Teresa and Dai, Hongzheng and Chiang, Theodore and Smith, Hadley and Azamian, Mahshid S and Robak, Laurie and Bostwick, Bret L and Schaaf, Christian P and Potocki, Lorraine and Scaglia, Fernando and Bacino, Carlos A and Hanchard, Neil A and Wangler, Michael F and Scott, Daryl and Brown, Chester and Hu, Jianhong and Belmont, John W and Burrage, Lindsay C and Graham, Brett H and Sutton, Vernon Reid and Craigen, William J and Plon, Sharon E and Lupski, James R and Beaudet, Arthur L and Gibbs, Richard A and Muzny, Donna M and Miller, Marcus J and Wang, Xia and Leduc, Magalie S and Xiao, Rui and Liu, Pengfei and Shaw, Chad and Walkiewicz, Magdalena and Bi, Weimin and Xia, Fan and Lee, Brendan and Eng, Christine M and Yang, Yaping and Lalani, Seema R} } @article {19, title = {Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.}, journal = {Genet Med}, volume = {19}, year = {2017}, month = {2017 Apr}, pages = {412-420}, abstract = {

PURPOSE: To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT).

METHODS: WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs).

RESULTS: In approximately 5\% of families, pathogenic SNVs were identified in PAX2, HNF1B, and EYA1. Observed phenotypes in these families expand the current understanding about the role of these genes in CAKUT. Four pathogenic CNVs were also identified using two CNV detection tools. In addition, we found one deleterious de novo SNV in FOXP1 among the 62 families with CAKUT. The clinical database of the Baylor Miraca Genetics laboratory was queried and seven additional unrelated individuals with novel de novo SNVs in FOXP1 were identified. Six of these eight individuals with FOXP1 SNVs have syndromic urinary tract defects, implicating this gene in urinary tract development.

CONCLUSION: We conclude that WES can be used to identify molecular etiology (SNVs, CNVs) in a subset of individuals with CAKUT. WES can also help identify novel CAKUT genes.Genet Med 19 4, 412-420.

}, keywords = {Adolescent, Child, Child, Preschool, DNA Copy Number Variations, Exome Sequencing, Female, Forkhead Transcription Factors, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 1-beta, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Nuclear Proteins, PAX2 Transcription Factor, Pedigree, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatases, Repressor Proteins, Urogenital Abnormalities, Vesico-Ureteral Reflux, Young Adult}, issn = {1530-0366}, doi = {10.1038/gim.2016.131}, author = {Bekheirnia, Mir Reza and Bekheirnia, Nasim and Bainbridge, Matthew N and Gu, Shen and Coban Akdemir, Zeynep Hande and Gambin, Tomek and Janzen, Nicolette K and Jhangiani, Shalini N and Muzny, Donna M and Michael, Mini and Brewer, Eileen D and Elenberg, Ewa and Kale, Arundhati S and Riley, Alyssa A and Swartz, Sarah J and Scott, Daryl A and Yang, Yaping and Srivaths, Poyyapakkam R and Wenderfer, Scott E and Bodurtha, Joann and Applegate, Carolyn D and Velinov, Milen and Myers, Angela and Borovik, Lior and Craigen, William J and Hanchard, Neil A and Rosenfeld, Jill A and Lewis, Richard Alan and Gonzales, Edmond T and Gibbs, Richard A and Belmont, John W and Roth, David R and Eng, Christine and Braun, Michael C and Lupski, James R and Lamb, Dolores J} } @article {20, title = {ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment.}, journal = {Proc Natl Acad Sci U S A}, volume = {113}, year = {2016}, month = {2016 Oct 04}, pages = {11289-11293}, abstract = {

Acyl CoA Oxidase 2 (ACOX2) encodes branched-chain acyl-CoA oxidase, a peroxisomal enzyme believed to be involved in the metabolism of branched-chain fatty acids and bile acid intermediates. Deficiency of this enzyme has not been described previously. We report an 8-y-old male with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Exome sequencing revealed a previously unidentified homozygous premature termination mutation (p.Y69*) in ACOX2 Immunohistochemistry confirmed the absence of ACOX2 expression in the patient{\textquoteright}s liver, and biochemical analysis showed marked elevation of intermediate bile acids upstream of ACOX2. These findings define a potentially treatable inborn error of bile acid biosynthesis caused by ACOX2 deficiency.

}, keywords = {Ataxia, Bile Acids and Salts, Child, Cognitive Dysfunction, Homozygote, Humans, Infant, Infant, Newborn, Liver, Liver Cirrhosis, Loss of Function Mutation, Male, Mutation, Oxidation-Reduction, Oxidoreductases, Transaminases}, issn = {1091-6490}, doi = {10.1073/pnas.1613228113}, author = {Vilarinho, S{\'\i}lvia and Sari, Sinan and Mazzacuva, Francesca and Bilguvar, Kaya and Esendagli-Yilmaz, G{\"u}ldal and Jain, Dhanpat and Akyol, G{\"u}len and Dalgi{\c c}, Buket and G{\"u}nel, Murat and Clayton, Peter T and Lifton, Richard P} } @article {14, title = {Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Nov 03}, pages = {1181-1189}, abstract = {

Cobblestone lissencephaly (COB) is a severe brain malformation in which overmigration of neurons and glial cells into the arachnoid space results in the formation of cortical dysplasia. COB occurs in a wide range of genetic disorders known as dystroglycanopathies, which are congenital muscular dystrophies associated with brain and eye anomalies and range from Walker-Warburg syndrome to Fukuyama congenital muscular dystrophy. Each of these conditions has been associated with alpha-dystroglycan defects or with mutations in genes encoding basement membrane components, which are known to interact with alpha-dystroglycan. Our screening of a cohort of 25 families with recessive forms of COB identified six families affected by biallelic mutations in TMTC3 (encoding transmembrane and tetratricopeptide repeat containing 3), a gene without obvious functional connections to alpha-dystroglycan. Most affected individuals showed brainstem and cerebellum hypoplasia, as well as ventriculomegaly. However, the minority of the affected individuals had eye defects or elevated muscle creatine phosphokinase, separating the TMTC3 COB phenotype from typical congenital muscular dystrophies. Our data suggest that loss of TMTC3 causes COB with minimal eye or muscle involvement.

}, keywords = {Alleles, Amino Acid Sequence, Basement Membrane, Brain, Carrier Proteins, Cerebellum, Cobblestone Lissencephaly, Developmental Disabilities, Dystroglycans, Eye Abnormalities, Female, Humans, Infant, Male, Membrane Proteins, Mutation, Nervous System Malformations, Neuroglia, Neurons, Pedigree, Phenotype}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.09.007}, author = {Jerber, Julie and Zaki, Maha S and Al-Aama, Jumana Y and Rosti, Rasim Ozgur and Ben-Omran, Tawfeg and Dikoglu, Esra and Silhavy, Jennifer L and Caglar, Caner and Musaev, Damir and Albrecht, Beate and Campbell, Kevin P and Willer, Tobias and Almuriekhi, Mariam and {\c C}a{\u g}layan, Ahmet Okay and Vajsar, Jiri and Bilguvar, Kaya and Ogur, Gonul and Abou Jamra, Rami and G{\"u}nel, Murat and Gleeson, Joseph G} } @article {30, title = {Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Aug 04}, pages = {318-36}, abstract = {

Bardet-Biedl syndrome (BBS) is a defining ciliopathy, notable for extensive allelic and genetic heterogeneity, almost all of which has been identified through sequencing. Recent data have suggested that copy-number variants (CNVs) also contribute to BBS. We used a custom oligonucleotide array comparative genomic hybridization (aCGH) covering 20 genes that encode intraflagellar transport (IFT) components and 74 ciliopathy loci to screen 92 unrelated individuals with BBS, irrespective of their known mutational burden. We identified 17 individuals with exon-disruptive CNVs (18.5\%), including 13 different deletions in eight BBS genes (BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, BBS9, and NPHP1) and a deletion and a duplication in other ciliopathy-associated genes (ALMS1 and NPHP4, respectively). By contrast, we found a single heterozygous exon-disruptive event in a BBS-associated gene (BBS9) in 229 control subjects. Superimposing these data with resequencing revealed CNVs to (1) be sufficient to cause disease, (2) Mendelize heterozygous deleterious alleles, and (3) contribute oligogenic alleles by combining point mutations and exonic CNVs in multiple genes. Finally, we report a deletion and a splice site mutation in IFT74, inherited under a recessive paradigm, defining a candidate BBS locus. Our data suggest that CNVs contribute pathogenic alleles to a substantial fraction of BBS-affected individuals and highlight how either deletions or point mutations in discrete splice isoforms can induce hypomorphic mutations in genes otherwise intolerant to deleterious variation. Our data also suggest that CNV analyses and resequencing studies unbiased for previous mutational burden is necessary to delineate the complexity of disease architecture.

}, keywords = {Adolescent, Adult, Alleles, Animals, Bardet-Biedl Syndrome, Child, Child, Preschool, Chromosome Breakpoints, Cytoskeletal Proteins, DNA Copy Number Variations, Exons, Female, Gastrulation, Genes, Recessive, Humans, Infant, Male, Mutation, Pedigree, Young Adult, Zebrafish, Zebrafish Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.04.023}, author = {Lindstrand, Anna and Frangakis, Stephan and Carvalho, Claudia M B and Richardson, Ellen B and McFadden, Kelsey A and Willer, Jason R and Pehlivan, Davut and Liu, Pengfei and Pediaditakis, Igor L and Sabo, Aniko and Lewis, Richard Alan and Banin, Eyal and Lupski, James R and Davis, Erica E and Katsanis, Nicholas} } @article {94, title = {Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension.}, journal = {Clin Genet}, volume = {90}, year = {2016}, month = {2016 10}, pages = {351-60}, abstract = {

Moyamoya disease (MMD) is a progressive vasculopathy characterized by occlusion of the terminal portion of the internal carotid arteries and its branches, and the formation of compensatory moyamoya collateral vessels. Homozygous mutations in GUCY1A3 have been reported as a cause of MMD and achalasia. Probands (n = 96) from unrelated families underwent sequencing of GUCY1A3. Functional studies were performed to confirm the pathogenicity of identified GUCY1A3 variants. Two affected individuals from the unrelated families were found to have compound heterozygous mutations in GUCY1A3. MM041 was diagnosed with achalasia at 4 years of age, hypertension and MMD at 18 years of age. MM149 was diagnosed with MMD and hypertension at the age of 20 months. Both individuals carry one allele that is predicted to lead to haploinsufficiency and a second allele that is predicted to produce a mutated protein. Biochemical studies of one of these alleles, GUCY1A3 Cys517Tyr, showed that the mutant protein (a subunit of soluble guanylate cyclase) has a significantly blunted signaling response with exposure to nitric oxide (NO). GUCY1A3 missense and haploinsufficiency mutations disrupt NO signaling leading to MMD and hypertension, with or without achalasia.

}, keywords = {Adolescent, Adult, Animals, Child, Child, Preschool, Cohort Studies, Esophageal Achalasia, Female, Humans, Hypertension, Infant, Male, Middle Aged, Moyamoya Disease, Mutation, Nitric Oxide, Nonlinear Dynamics, Regression Analysis, Sf9 Cells, Signal Transduction, Soluble Guanylyl Cyclase}, issn = {1399-0004}, doi = {10.1111/cge.12739}, author = {Wallace, S and Guo, D-C and Regalado, E and Mellor-Crummey, L and Bamshad, M and Nickerson, D A and Dauser, R and Hanchard, N and Marom, R and Martin, E and Berka, V and Sharina, I and Ganesan, V and Saunders, D and Morris, S A and Milewicz, D M} } @article {114, title = {Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 Jan 15}, pages = {348-57}, abstract = {

Disorders of keratinization (DOK) show marked genotypic and phenotypic heterogeneity. In most cases, disease is primarily cutaneous, and further clinical evaluation is therefore rarely pursued. We have identified subjects with a novel DOK featuring erythrokeratodermia and initially-asymptomatic, progressive, potentially fatal cardiomyopathy, a finding not previously associated with erythrokeratodermia. We show that de novo missense mutations clustered tightly within a single spectrin repeat of DSP cause this novel cardio-cutaneous disorder, which we term erythrokeratodermia-cardiomyopathy (EKC) syndrome. We demonstrate that DSP mutations in our EKC syndrome subjects affect localization of desmosomal proteins and connexin 43 in the skin, and result in desmosome aggregation, widening of intercellular spaces, and lipid secretory defects. DSP encodes desmoplakin, a primary component of desmosomes, intercellular adhesion junctions most abundant in the epidermis and heart. Though mutations in DSP are known to cause other disorders, our cohort features the unique clinical finding of severe whole-body erythrokeratodermia, with distinct effects on localization of desmosomal proteins and connexin 43. These findings add a severe, previously undescribed syndrome featuring erythrokeratodermia and cardiomyopathy to the spectrum of disease caused by mutation in DSP, and identify a specific region of the protein critical to the pathobiology of EKC syndrome and to DSP function in the heart and skin.

}, keywords = {Amino Acid Sequence, Cardiomyopathies, Child, Child, Preschool, Connexin 43, Desmoplakins, Desmosomes, Female, Humans, Infant, Male, Molecular Sequence Data, Mutation, Missense, Myocardium, Protein Transport, Sequence Alignment, Skin, Skin Diseases, Genetic, Syndrome}, issn = {1460-2083}, doi = {10.1093/hmg/ddv481}, author = {Boyden, Lynn M and Kam, Chen Y and Hern{\'a}ndez-Mart{\'\i}n, Angela and Zhou, Jing and Craiglow, Brittany G and Sidbury, Robert and Mathes, Erin F and Maguiness, Sheilagh M and Crumrine, Debra A and Williams, Mary L and Hu, Ronghua and Lifton, Richard P and Elias, Peter M and Green, Kathleen J and Choate, Keith A} } @article {65, title = {Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 05 05}, pages = {1001-1010}, abstract = {

Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding protein~subunit beta-1, Gβ. These 13 individuals were identified among a base of 5,855 individuals recruited for various undiagnosed genetic disorders. The probability of observing 13 or more de novo mutations by chance among 5,855 individuals is very low (p~=~7.1~{\texttimes} 10(-21)), implicating GNB1 as a genome-wide-significant disease-associated gene. The majority of these 13 mutations affect known Gβ binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for Gα-Gβγ interaction (resulting in a constitutively active Gβγ) or through the disruption of residues relevant for interaction between Gβγ and certain downstream effectors (resulting in reduced interaction with the effectors). Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Developmental Disabilities, Exome, Female, Germ-Line Mutation, GTP-Binding Protein beta Subunits, Humans, Infant, Intellectual Disability, Male, Muscle Hypotonia, Phenotype, Protein Conformation, Seizures, Signal Transduction, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.03.011}, author = {Petrovski, Slav{\'e} and K{\"u}ry, S{\'e}bastien and Myers, Candace T and Anyane-Yeboa, Kwame and Cogn{\'e}, Benjamin and Bialer, Martin and Xia, Fan and Hemati, Parisa and Riviello, James and Mehaffey, Michele and Besnard, Thomas and Becraft, Emily and Wadley, Alexandrea and Politi, Anya Revah and Colombo, Sophie and Zhu, Xiaolin and Ren, Zhong and Andrews, Ian and Dudding-Byth, Tracy and Schneider, Amy L and Wallace, Geoffrey and Rosen, Aaron B I and Schelley, Susan and Enns, Gregory M and Corre, Pierre and Dalton, Joline and Mercier, Sandra and Latypova, X{\'e}nia and Schmitt, S{\'e}bastien and Guzman, Edwin and Moore, Christine and Bier, Louise and Heinzen, Erin L and Karachunski, Peter and Shur, Natasha and Grebe, Theresa and Basinger, Alice and Nguyen, Joanne M and B{\'e}zieau, St{\'e}phane and Wierenga, Klaas and Bernstein, Jonathan A and Scheffer, Ingrid E and Rosenfeld, Jill A and Mefford, Heather C and Isidor, Bertrand and Goldstein, David B} } @article {50, title = {Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.}, journal = {Acta Neuropathol Commun}, volume = {4}, year = {2016}, month = {2016 06 01}, pages = {56}, abstract = {

Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8~\%) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101\&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial~acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.

}, keywords = {Acromegaly, Adenoma, Adolescent, Child, Child, Preschool, Female, Gene Duplication, Germ-Line Mutation, Gigantism, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Pituitary Neoplasms, Receptors, G-Protein-Coupled, Treatment Outcome, Young Adult}, issn = {2051-5960}, doi = {10.1186/s40478-016-0328-1}, author = {Iacovazzo, Donato and Caswell, Richard and Bunce, Benjamin and Jose, Sian and Yuan, Bo and Hern{\'a}ndez-Ram{\'\i}rez, Laura C and Kapur, Sonal and Caimari, Francisca and Evanson, Jane and Ferra{\`u}, Francesco and Dang, Mary N and Gabrovska, Plamena and Larkin, Sarah J and Ansorge, Olaf and Rodd, Celia and Vance, Mary L and Ram{\'\i}rez-Renteria, Claudia and Mercado, Mois{\'e}s and Goldstone, Anthony P and Buchfelder, Michael and Burren, Christine P and Gurlek, Alper and Dutta, Pinaki and Choong, Catherine S and Cheetham, Timothy and Trivellin, Giampaolo and Stratakis, Constantine A and Lopes, Maria-Beatriz and Grossman, Ashley B and Trouillas, Jacqueline and Lupski, James R and Ellard, Sian and Sampson, Julian R and Roncaroli, Federico and Korbonits, M{\'a}rta} } @article {33, title = {GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Aug 04}, pages = {443-50}, abstract = {

Vascular tumors are among the most common neoplasms in infants and children; 5\%-10\% of newborns present with or develop lesions within the first 3~months of life. Most are benign infantile hemangiomas that typically regress by 5 years of age; other vascular tumors include congenital tufted angiomas (TAs), kaposiform hemangioendotheliomas (KHEs), and childhood lobular capillary hemangiomas (LCHs). Some of these lesions can become locally invasive and unresponsive to pharmacologic intervention, leading to significant complications. Recent investigation has revealed that activating mutations in HRAS, KRAS, NRAS, GNAQ, and GNA11 can cause certain types of rare childhood vascular tumors, and we have now identified causal recurrent somatic activating mutations in GNA14 by whole-exome and targeted sequencing. We found somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations in one KHE, one TA, and one LCH and a GNA11 c.547C>T (p.Arg183Cys) mutation in two LCH lesions. We examined mutation pathobiology via expression of mutant GNA14 or GNA11 in primary human endothelial cells and melanocytes. GNA14 and GNA11 mutations induced changes in cellular morphology and rendered cells growth-factor independent by upregulating the MAPK pathway. Our findings identify GNA14 mutations as a cause of childhood vascular tumors, offer insight into mechanisms of oncogenic transformation by mutations affecting Gaq family members, and identify potential targets for therapeutic intervention.

}, keywords = {Cells, Cultured, Child, Preschool, Enzyme Activation, GTP-Binding Protein alpha Subunits, GTP-Binding Protein alpha Subunits, Gq-G11, Human Umbilical Vein Endothelial Cells, Humans, Infant, Infant, Newborn, Intercellular Signaling Peptides and Proteins, Male, MAP Kinase Signaling System, Melanocytes, Mitogen-Activated Protein Kinases, Mutation, Proto-Oncogene Proteins c-akt, Vascular Neoplasms}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.06.010}, author = {Lim, Young H and Bacchiocchi, Antonella and Qiu, Jingyao and Straub, Robert and Bruckner, Anna and Bercovitch, Lionel and Narayan, Deepak and McNiff, Jennifer and Ko, Christine and Robinson-Bostom, Leslie and Antaya, Richard and Halaban, Ruth and Choate, Keith A} } @article {117, title = {Identification and clinical characterization of Hermansky-Pudlak syndrome alleles in the Pakistani population.}, journal = {Pigment Cell Melanoma Res}, volume = {29}, year = {2016}, month = {2016 Mar}, pages = {231-5}, keywords = {Adolescent, Adult, Alleles, Child, Child, Preschool, Female, Hermanski-Pudlak Syndrome, Humans, Infant, Male, Membrane Proteins, Middle Aged, Pakistan, Pedigree}, issn = {1755-148X}, doi = {10.1111/pcmr.12438}, author = {Yousaf, Sairah and Shahzad, Mohsin and Kausar, Tasleem and Sheikh, Shakeel A and Tariq, Nabeela and Shabbir, Asra S and Ali, Muhammad and Waryah, Ali M and Shaikh, Rehan S and Riazuddin, Saima and Ahmed, Zubair M} } @article {410, title = {Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.}, journal = {Cell}, volume = {167}, year = {2016}, month = {2016 Dec 01}, pages = {1481-1494.e18}, abstract = {

Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.

}, keywords = {Amino Acids, Animals, Autism Spectrum Disorder, Blood-Brain Barrier, Brain, Female, Humans, Infant, Infant, Newborn, Large Neutral Amino Acid-Transporter 1, Male, Mice, Mice, Knockout, Mutation, Pedigree, Protein Biosynthesis, Receptor, TIE-2}, issn = {1097-4172}, doi = {10.1016/j.cell.2016.11.013}, author = {T{\u a}rlungeanu, Dora C and Deliu, Elena and Dotter, Christoph P and Kara, Majdi and Janiesch, Philipp Christoph and Scalise, Mariafrancesca and Galluccio, Michele and Tesulov, Mateja and Morelli, Emanuela and Sonmez, Fatma Mujgan and Bilguvar, Kaya and Ohgaki, Ryuichi and Kanai, Yoshikatsu and Johansen, Anide and Esharif, Seham and Ben-Omran, Tawfeg and Topcu, Meral and Schlessinger, Avner and Indiveri, Cesare and Duncan, Kent E and {\c C}a{\u g}layan, Ahmet Okay and G{\"u}nel, Murat and Gleeson, Joseph G and Novarino, Gaia} } @article {343, title = {An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 09 15}, pages = {3998-4011}, abstract = {

The short rib polydactyly syndromes (SRPS) are a group of recessively inherited, perinatal-lethal skeletal disorders primarily characterized by short ribs, shortened long bones, varying types of polydactyly and concomitant visceral abnormalities. Mutations in several genes affecting cilia function cause SRPS, revealing a role for cilia function in skeletal development. To identify additional SRPS genes and discover novel ciliary molecules required for normal skeletogenesis, we performed exome sequencing in a cohort of patients and identified homozygosity for a missense mutation, p.E80K, in Intestinal Cell Kinase, ICK, in one SRPS family. The p.E80K mutation abolished serine/threonine kinase activity, resulting in altered ICK subcellular and ciliary localization, increased cilia length, aberrant cartilage growth plate structure, defective Hedgehog and altered ERK signalling. These data identify ICK as an SRPS-associated gene and reveal that abnormalities in signalling pathways contribute to defective skeletogenesis.

}, keywords = {Abnormalities, Multiple, Cilia, Exome, Female, Hedgehog Proteins, Humans, Infant, MAP Kinase Signaling System, Pedigree, Pregnancy, Protein-Serine-Threonine Kinases, Sequence Analysis, DNA, Short Rib-Polydactyly Syndrome, Signal Transduction, Skeleton}, issn = {1460-2083}, doi = {10.1093/hmg/ddw240}, author = {Paige Taylor, S and Kunova Bosakova, Michaela and Varecha, Miroslav and Balek, Lukas and Barta, Tomas and Trantirek, Lukas and Jelinkova, Iva and Duran, Ivan and Vesela, Iva and Forlenza, Kimberly N and Martin, Jorge H and Hampl, Ales and Bamshad, Michael and Nickerson, Deborah and Jaworski, Margie L and Song, Jieun and Ko, Hyuk Wan and Cohn, Daniel H and Krakow, Deborah and Krejci, Pavel} } @article {36, title = {KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction.}, journal = {Ann Neurol}, volume = {80}, year = {2016}, month = {2016 Oct}, pages = {633-7}, abstract = {

Missense mutations in kinesin family member 5A (KIF5A) cause spastic paraplegia 10. We report on 2 patients with de novo stop-loss frameshift variants in KIF5A resulting in a novel phenotype that includes severe infantile onset myoclonus, hypotonia, optic nerve abnormalities, dysphagia, apnea, and early developmental arrest. We propose that alteration and elongation of the carboxy-terminus of the protein has a dominant-negative effect, causing mitochondrial dysfunction in the setting of an abnormal kinesin "motor." These results highlight the role of expanded testing and whole-exome sequencing in critically ill infants and emphasize the importance of accurate test interpretation. Ann Neurol 2016;80:633-637.

}, keywords = {Apnea, Child, Preschool, Deglutition Disorders, Developmental Disabilities, Fatal Outcome, Female, Frameshift Mutation, Humans, Infant, Kinesins, Male, Mitochondrial Diseases, Muscle Hypotonia, Mutation, Myoclonus, Optic Nerve}, issn = {1531-8249}, doi = {10.1002/ana.24744}, author = {Duis, Jessica and Dean, Shannon and Applegate, Carolyn and Harper, Amy and Xiao, Rui and He, Weimin and Dollar, James D and Sun, Lisa R and Waberski, Marta Biderman and Crawford, Thomas O and Hamosh, Ada and Stafstrom, Carl E} } @article {51, title = {Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 06 02}, pages = {1249-1255}, abstract = {

Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.

}, keywords = {alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Brain Diseases, Electrophysiology, Epilepsy, Female, Humans, Hyperkinesis, Infant, Male, Membrane Proteins, Mutation, Nerve Tissue Proteins, Pedigree, Synaptic Transmission}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.04.008}, author = {Madeo, Marianna and Stewart, Michelle and Sun, Yuyang and Sahir, Nadia and Wiethoff, Sarah and Chandrasekar, Indra and Yarrow, Anna and Rosenfeld, Jill A and Yang, Yaping and Cordeiro, Dawn and McCormick, Elizabeth M and Muraresku, Colleen C and Jepperson, Tyler N and McBeth, Lauren J and Seidahmed, Mohammed Zain and El Khashab, Heba Y and Hamad, Muddathir and Azzedine, Hamid and Clark, Karl and Corrochano, Silvia and Wells, Sara and Elting, Mariet W and Weiss, Marjan M and Burn, Sabrina and Myers, Angela and Landsverk, Megan and Crotwell, Patricia L and Waisfisz, Quinten and Wolf, Nicole I and Nolan, Patrick M and Padilla-Lopez, Sergio and Houlden, Henry and Lifton, Richard and Mane, Shrikant and Singh, Brij B and Falk, Marni J and Mercimek-Mahmutoglu, Saadet and Bilguvar, Kaya and Salih, Mustafa A and Acevedo-Arozena, Abraham and Kruer, Michael C} } @article {119, title = {Mechanisms for the Generation of Two Quadruplications Associated with Split-Hand Malformation.}, journal = {Hum Mutat}, volume = {37}, year = {2016}, month = {2016 Feb}, pages = {160-4}, abstract = {

Germline copy-number variants (CNVs) involving quadruplications are rare and the mechanisms generating them are largely unknown. Previously, we reported a 20-week gestation fetus with split-hand malformation; clinical microarray detected two maternally inherited triplications separated by a copy-number neutral region at 17p13.3, involving BHLHA9 and part of YWHAE. Here, we describe an 18-month-old male sibling of the previously described fetus with split-hand malformation. Custom high-density microarray and digital droplet PCR revealed the copy-number gains were actually quadruplications in the mother, the fetus, and her later born son. This quadruplication-normal-quadruplication pattern was shown to be expanded from the triplication-normal-triplication CNV at the same loci in the maternal grandmother. We mapped two breakpoint junctions and demonstrated that both are mediated by Alu repetitive elements and identical in these four individuals. We propose a three-step process combining Alu-mediated replicative-repair-based mechanism(s) and intergenerational, intrachromosomal nonallelic homologous recombination to generate the quadruplications in this family.

}, keywords = {14-3-3 Proteins, Adult, Aged, Alu Elements, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, Chromosome Duplication, Chromosomes, Human, Pair 17, DNA Copy Number Variations, Female, Genetic Loci, Genome, Human, Hand Deformities, Congenital, Humans, Infant, Male, Molecular Sequence Data, Pedigree, Sequence Alignment, Sequence Analysis, DNA}, issn = {1098-1004}, doi = {10.1002/humu.22929}, author = {Gu, Shen and Posey, Jennifer E and Yuan, Bo and Carvalho, Claudia M B and Luk, H M and Erikson, Kelly and Lo, Ivan F M and Leung, Gordon K C and Pickering, Curtis R and Chung, Brian H Y and Lupski, James R} } @article {342, title = {MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Dec 01}, pages = {1229-1244}, abstract = {

Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285), c.247_250del (p.Asn83Hisfs4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.

}, keywords = {Basal Ganglia, Cells, Cultured, Child, Child, Preschool, Dystonic Disorders, Fatty Acids, Female, Fibroblasts, Genetic Complementation Test, Humans, Infant, Male, Mitochondria, Mitochondrial Diseases, Models, Molecular, Mutation, Mutation, Missense, Optic Atrophy, Oxidoreductases Acting on CH-CH Group Donors, Pedigree, RNA Splice Sites, Saccharomyces cerevisiae}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.09.021}, author = {Heimer, Gali and Ker{\"a}t{\"a}r, Juha M and Riley, Lisa G and Balasubramaniam, Shanti and Eyal, Eran and Pietik{\"a}inen, Laura P and Hiltunen, J Kalervo and Marek-Yagel, Dina and Hamada, Jeffrey and Gregory, Allison and Rogers, Caleb and Hogarth, Penelope and Nance, Martha A and Shalva, Nechama and Veber, Alvit and Tzadok, Michal and Nissenkorn, Andreea and Tonduti, Davide and Renaldo, Florence and Kraoua, Ichraf and Panteghini, Celeste and Valletta, Lorella and Garavaglia, Barbara and Cowley, Mark J and Gayevskiy, Velimir and Roscioli, Tony and Silberstein, Jonathon M and Hoffmann, Chen and Raas-Rothschild, Annick and Tiranti, Valeria and Anikster, Yair and Christodoulou, John and Kastaniotis, Alexander J and Ben-Zeev, Bruria and Hayflick, Susan J} } @article {10, title = {MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death.}, journal = {Genome Med}, volume = {8}, year = {2016}, month = {2016 Nov 01}, pages = {106}, abstract = {

BACKGROUND: Mitochondrial presequence proteases perform fundamental functions as they process about 70~\% of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease.

METHODS: Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human.

RESULTS: Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients{\textquoteright} missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria.

CONCLUSIONS: Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.

}, keywords = {Adult, Amino Acid Sequence, Female, Genes, Recessive, Heart Defects, Congenital, Humans, Infant, Infant, Newborn, Male, Metalloendopeptidases, Muscle Hypotonia, Pedigree, Phenotype, Sequence Homology, Amino Acid, Sudden Infant Death, Syndrome}, issn = {1756-994X}, doi = {10.1186/s13073-016-0360-6}, author = {Eldomery, Mohammad K and Akdemir, Zeynep C and V{\"o}gtle, F-Nora and Charng, Wu-Lin and Mulica, Patrycja and Rosenfeld, Jill A and Gambin, Tomasz and Gu, Shen and Burrage, Lindsay C and Al Shamsi, Aisha and Penney, Samantha and Jhangiani, Shalini N and Zimmerman, Holly H and Muzny, Donna M and Wang, Xia and Tang, Jia and Medikonda, Ravi and Ramachandran, Prasanna V and Wong, Lee-Jun and Boerwinkle, Eric and Gibbs, Richard A and Eng, Christine M and Lalani, Seema R and Hertecant, Jozef and Rodenburg, Richard J and Abdul-Rahman, Omar A and Yang, Yaping and Xia, Fan and Wang, Meng C and Lupski, James R and Meisinger, Chris and Sutton, V Reid} } @article {74, title = {Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Mar 03}, pages = {579-587}, abstract = {

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, although affected individuals without seizures and with normal intellect have also been reported. Given the patchy and asymmetric nature of the malformations, ECCL has been hypothesized to be due to a post-zygotic, mosaic mutation. Despite phenotypic overlap with several other disorders associated with mutations in the RAS-MAPK and PI3K-AKT pathways, the molecular etiology of ECCL remains unknown. Using exome sequencing of DNA from multiple affected tissues from five unrelated individuals with ECCL, we identified two mosaic mutations, c.1638C>A (p.Asn546Lys) and c.1966A>G (p.Lys656Glu) within the tyrosine kinase domain of FGFR1, in two affected individuals each. These two residues are the most commonly mutated residues in FGFR1 in human cancers and are associated primarily with CNS tumors. Targeted resequencing of FGFR1 in multiple tissues from an independent cohort of individuals with ECCL identified one additional individual with a c.1638C>A (p.Asn546Lys) mutation in FGFR1. Functional studies of ECCL fibroblast cell lines show increased levels of phosphorylated FGFRs and phosphorylated FRS2, a direct substrate of FGFR1, as well as constitutive activation of RAS-MAPK signaling. In addition to identifying the molecular etiology of ECCL, our results support the emerging overlap between mosaic developmental disorders and tumorigenesis.

}, keywords = {Adolescent, Cell Line, Tumor, Central Nervous System Neoplasms, Child, Preschool, Exome, Eye, Eye Diseases, Female, Humans, Infant, Lipomatosis, Male, Mutation, Mutation, Missense, Neurocutaneous Syndromes, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptor, Fibroblast Growth Factor, Type 1, Seizures, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.02.006}, author = {Bennett, James T and Tan, Tiong Yang and Alcantara, Diana and T{\'e}trault, Martine and Timms, Andrew E and Jensen, Dana and Collins, Sarah and Nowaczyk, Malgorzata J M and Lindhurst, Marjorie J and Christensen, Katherine M and Braddock, Stephen R and Brandling-Bennett, Heather and Hennekam, Raoul C M and Chung, Brian and Lehman, Anna and Su, John and Ng, SuYuen and Amor, David J and Majewski, Jacek and Biesecker, Les G and Boycott, Kym M and Dobyns, William B and O{\textquoteright}Driscoll, Mark and Moog, Ute and McDonell, Laura M} } @article {23, title = {Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Oct 06}, pages = {912-916}, abstract = {

The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features.

}, keywords = {Acyltransferases, Arachidonic Acid, Autistic Disorder, Child, Child, Preschool, Consanguinity, Epilepsy, Female, Homozygote, Humans, Infant, Intellectual Disability, Lysophospholipids, Male, Membrane Proteins, Mutation, Pedigree, Phosphatidylinositols}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.07.019}, author = {Johansen, Anide and Rosti, Rasim O and Musaev, Damir and Sticca, Evan and Harripaul, Ricardo and Zaki, Maha and {\c C}a{\u g}layan, Ahmet Okay and Azam, Matloob and Sultan, Tipu and Froukh, Tawfiq and Reis, Andr{\'e} and Popp, Bernt and Ahmed, Iltaf and John, Peter and Ayub, Muhammad and Ben-Omran, Tawfeg and Vincent, John B and Gleeson, Joseph G and Abou Jamra, Rami} } @article {84, title = {Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 Apr}, pages = {457-65}, abstract = {

Nucleoporins are essential components of the nuclear pore complex (NPC). Only a few diseases have been attributed to NPC dysfunction. Steroid-resistant nephrotic syndrome (SRNS), a frequent cause of chronic kidney disease, is caused by dysfunction of glomerular podocytes. Here we identify in eight families with SRNS mutations in NUP93, its interaction partner NUP205 or XPO5 (encoding exportin 5) as hitherto unrecognized monogenic causes of SRNS. NUP93 mutations caused disrupted NPC assembly. NUP93 knockdown reduced the presence of NUP205 in the NPC, and, reciprocally, a NUP205 alteration abrogated NUP93 interaction. We demonstrate that NUP93 and exportin 5 interact with the signaling protein SMAD4 and that NUP93 mutations abrogated interaction with SMAD4. Notably, NUP93 mutations interfered with BMP7-induced SMAD transcriptional reporter activity. We hereby demonstrate that mutations of NUP genes cause a distinct renal disease and identify aberrant SMAD signaling as a new disease mechanism of SRNS, opening a potential new avenue for treatment.

}, keywords = {Age of Onset, Amino Acid Sequence, Animals, Cell Movement, Cell Proliferation, Cells, Cultured, Child, Child, Preschool, Drug Resistance, Female, Genes, Recessive, Genetic Association Studies, Genetic Linkage, HEK293 Cells, Humans, Infant, Karyopherins, Male, Mice, Molecular Sequence Data, Mutation, Nephrotic Syndrome, Nuclear Pore Complex Proteins, Oxidative Stress, Podocytes, Sequence Analysis, DNA, Steroids, Xenopus laevis}, issn = {1546-1718}, doi = {10.1038/ng.3512}, author = {Braun, Daniela A and Sadowski, Carolin E and Kohl, Stefan and Lovric, Svjetlana and Astrinidis, Susanne A and Pabst, Werner L and Gee, Heon Yung and Ashraf, Shazia and Lawson, Jennifer A and Shril, Shirlee and Airik, Merlin and Tan, Weizhen and Schapiro, David and Rao, Jia and Choi, Won-Il and Hermle, Tobias and Kemper, Markus J and Pohl, Martin and Ozaltin, Fatih and Konrad, Martin and Bogdanovic, Radovan and B{\"u}scher, Rainer and Helmchen, Udo and Serdaroglu, Erkin and Lifton, Richard P and Antonin, Wolfram and Hildebrandt, Friedhelm} } @article {44, title = {PEHO Syndrome May Represent Phenotypic Expansion at the Severe End of the Early-Onset Encephalopathies.}, journal = {Pediatr Neurol}, volume = {60}, year = {2016}, month = {2016 Jul}, pages = {83-7}, abstract = {

BACKGROUND: Progressive encephalopathy with edema, hypsarrhythmia and optic atrophy (PEHO) syndrome is a distinct neurodevelopmental disorder. Patients without optic nerve atrophy and brain imaging abnormalities but fulfilling other PEHO criteria are often described as a PEHO-like syndrome. The molecular bases of both clinically defined conditions remain unknown in spite of the widespread application of genome analyses in both clinic and research.

METHODS: We enrolled two patients with a prior diagnosis of PEHO and two individuals with PEHO-like syndrome. All four individuals subsequently underwent whole-exome sequencing and comprehensive genomic analysis.

RESULTS: We identified disease-causing mutations in known genes associated with neurodevelopmental disorders including GNAO1 and CDKL5 in two of four individuals. One patient with PEHO syndrome and a de novoGNAO1 mutation was found to have an additional de novo mutation in HESX1 that is associated with optic atrophy.

CONCLUSIONS: We hypothesize that PEHO and PEHO-like syndrome may represent a severe end of the spectrum of the early-onset encephalopathies and, in some instances, its complex phenotype may result from an aggregated effect of mutations at two loci.

}, keywords = {Brain Edema, Child, Child, Preschool, Female, GTP-Binding Protein alpha Subunits, Gi-Go, Humans, Infant, Male, Mutation, Neurodegenerative Diseases, Optic Atrophy, Phenotype, Protein Serine-Threonine Kinases, Spasms, Infantile}, issn = {1873-5150}, doi = {10.1016/j.pediatrneurol.2016.03.011}, author = {Gawlinski, Pawel and Posmyk, Renata and Gambin, Tomasz and Sielicka, Danuta and Chorazy, Monika and Nowakowska, Beata and Jhangiani, Shalini N and Muzny, Donna M and Bekiesinska-Figatowska, Monika and Bal, Jerzy and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R and Wiszniewski, Wojciech} } @article {97, title = {POGZ truncating alleles cause syndromic intellectual disability.}, journal = {Genome Med}, volume = {8}, year = {2016}, month = {2016 Jan 06}, pages = {3}, abstract = {

BACKGROUND: Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; however, detailed phenotypic information is often lacking in such studies. De novo mutations in pogo transposable element with zinc finger domain (POGZ) have been identified in six independent and diverse cohorts of individuals with NDDs ranging from autism spectrum disorder to developmental delay.

METHODS: Whole exome sequencing was performed on five unrelated individuals. Sanger sequencing was used to validate variants and segregate mutations with the phenotype in available family members.

RESULTS: We identified heterozygous truncating mutations in POGZ in five unrelated individuals, which were confirmed to be de novo or not present in available parental samples. Careful review of the phenotypes revealed shared features that included developmental delay, intellectual disability, hypotonia, behavioral abnormalities, and similar facial characteristics. Variable features included short stature, microcephaly, strabismus and hearing loss.

CONCLUSIONS: While POGZ has been associated with neurodevelopmental disorders in large cohort studies, our data suggest that loss of function variants in POGZ lead to an identifiable syndrome of NDD with specific phenotypic traits. This study exemplifies the era of human reverse clinical genomics ushered in by large disease-directed cohort studies; first defining a new syndrome molecularly and, only subsequently, phenotypically.

}, keywords = {Adolescent, Adult, Alleles, Child, Preschool, Exome, Female, Heterozygote, Humans, Infant, Intellectual Disability, Male, Mutation, Sequence Analysis, DNA, Transposases}, issn = {1756-994X}, doi = {10.1186/s13073-015-0253-0}, author = {White, Janson and Beck, Christine R and Harel, Tamar and Posey, Jennifer E and Jhangiani, Shalini N and Tang, Sha and Farwell, Kelly D and Powis, Z{\"o}e and Mendelsohn, Nancy J and Baker, Janice A and Pollack, Lynda and Mason, Kati J and Wierenga, Klaas J and Arrington, Daniel K and Hall, Melissa and Psychogios, Apostolos and Fairbrother, Laura and Walkiewicz, Magdalena and Person, Richard E and Niu, Zhiyv and Zhang, Jing and Rosenfeld, Jill A and Muzny, Donna M and Eng, Christine and Beaudet, Arthur L and Lupski, James R and Boerwinkle, Eric and Gibbs, Richard A and Yang, Yaping and Xia, Fan and Sutton, V Reid} } @article {63, title = {PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive.}, journal = {Ann Neurol}, volume = {80}, year = {2016}, month = {2016 07}, pages = {59-70}, abstract = {

OBJECTIVE: A study was undertaken to characterize the clinical features of the newly described hypomyelinating leukodystrophy type 10 with microcephaly. This is an autosomal recessive disorder mapped to chromosome 1q42.12 due to mutations in the PYCR2 gene, encoding an enzyme involved in proline synthesis in mitochondria.

METHODS: From several international clinics, 11 consanguineous families were identified with PYCR2 mutations by whole exome or targeted sequencing, with detailed clinical and radiological phenotyping. Selective mutations from patients were tested for effect on protein function.

RESULTS: The characteristic clinical presentation of patients with PYCR2 mutations included failure to thrive, microcephaly, craniofacial dysmorphism, progressive psychomotor disability, hyperkinetic movements, and axial hypotonia with variable appendicular spasticity. Patients did not survive beyond the first decade of life. Brain magnetic resonance imaging showed global brain atrophy and white matter T2 hyperintensities. Routine serum metabolic profiles were unremarkable. Both nonsense and missense mutations were identified, which impaired protein multimerization.

INTERPRETATION: PYCR2-related syndrome represents a clinically recognizable condition in which PYCR2 mutations lead to protein dysfunction, not detectable on routine biochemical assessments. Mutations predict a poor outcome, probably as a result of impaired mitochondrial function. Ann Neurol 2016;80:59-70.

}, keywords = {Adolescent, Child, Child, Preschool, Codon, Nonsense, Exome, Failure to Thrive, Female, Fibroblasts, Gene Expression, Genetic Predisposition to Disease, Genotype, Humans, Infant, Male, Microcephaly, Mutation, Missense, Phenotype, Primary Cell Culture, Pyrroline Carboxylate Reductases, Syndrome, Transfection, Young Adult}, issn = {1531-8249}, doi = {10.1002/ana.24678}, author = {Zaki, Maha S and Bhat, Gifty and Sultan, Tipu and Issa, Mahmoud and Jung, Hea-Jin and Dikoglu, Esra and Selim, Laila and G Mahmoud, Imam and Abdel-Hamid, Mohamed S and Abdel-Salam, Ghada and Marin-Valencia, Isaac and Gleeson, Joseph G} } @article {21, title = {Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Oct 06}, pages = {831-845}, abstract = {

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of bor, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of bor resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

}, keywords = {Adenosine Triphosphatases, Adult, Alleles, Animals, ATPases Associated with Diverse Cellular Activities, Axons, Cardiomyopathies, Child, Child, Preschool, Developmental Disabilities, DNA Copy Number Variations, Drosophila melanogaster, Female, Fibroblasts, Homozygote, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Muscle Hypotonia, Muscles, Mutation, Nervous System Diseases, Neurons, Optic Atrophy, Phenotype, Polymorphism, Single Nucleotide, Syndrome, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.08.007}, author = {Harel, Tamar and Yoon, Wan Hee and Garone, Caterina and Gu, Shen and Coban-Akdemir, Zeynep and Eldomery, Mohammad K and Posey, Jennifer E and Jhangiani, Shalini N and Rosenfeld, Jill A and Cho, Megan T and Fox, Stephanie and Withers, Marjorie and Brooks, Stephanie M and Chiang, Theodore and Duraine, Lita and Erdin, Serkan and Yuan, Bo and Shao, Yunru and Moussallem, Elie and Lamperti, Costanza and Donati, Maria A and Smith, Joshua D and McLaughlin, Heather M and Eng, Christine M and Walkiewicz, Magdalena and Xia, Fan and Pippucci, Tommaso and Magini, Pamela and Seri, Marco and Zeviani, Massimo and Hirano, Michio and Hunter, Jill V and Srour, Myriam and Zanigni, Stefano and Lewis, Richard Alan and Muzny, Donna M and Lotze, Timothy E and Boerwinkle, Eric and Gibbs, Richard A and Hickey, Scott E and Graham, Brett H and Yang, Yaping and Buhas, Daniela and Martin, Donna M and Potocki, Lorraine and Graziano, Claudio and Bellen, Hugo J and Lupski, James R} } @article {90, title = {Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Feb 04}, pages = {347-57}, abstract = {

The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous \~{}34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.

}, keywords = {Alleles, Arabs, Arrhythmias, Cardiac, Base Sequence, Child, Child, Preschool, Endoplasmic Reticulum Stress, European Continental Ancestry Group, Exome, Exons, Female, Gene Deletion, Golgi Apparatus, Hispanic Americans, Homozygote, Humans, Infant, Male, Molecular Sequence Data, Muscle Weakness, Pedigree, Rhabdomyolysis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.12.008}, author = {Lalani, Seema R and Liu, Pengfei and Rosenfeld, Jill A and Watkin, Levi B and Chiang, Theodore and Leduc, Magalie S and Zhu, Wenmiao and Ding, Yan and Pan, Shujuan and Vetrini, Francesco and Miyake, Christina Y and Shinawi, Marwan and Gambin, Tomasz and Eldomery, Mohammad K and Akdemir, Zeynep Hande Coban and Emrick, Lisa and Wilnai, Yael and Schelley, Susan and Koenig, Mary Kay and Memon, Nada and Farach, Laura S and Coe, Bradley P and Azamian, Mahshid and Hernandez, Patricia and Zapata, Gladys and Jhangiani, Shalini N and Muzny, Donna M and Lotze, Timothy and Clark, Gary and Wilfong, Angus and Northrup, Hope and Adesina, Adekunle and Bacino, Carlos A and Scaglia, Fernando and Bonnen, Penelope E and Crosson, Jane and Duis, Jessica and Maegawa, Gustavo H B and Coman, David and Inwood, Anita and McGill, Jim and Boerwinkle, Eric and Graham, Brett and Beaudet, Art and Eng, Christine M and Hanchard, Neil A and Xia, Fan and Orange, Jordan S and Gibbs, Richard A and Lupski, James R and Yang, Yaping} } @article {85, title = {Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.}, journal = {Hepatology}, volume = {63}, year = {2016}, month = {2016 06}, pages = {1977-86}, abstract = {

UNLABELLED: Despite advances in the diagnosis and management of idiopathic noncirrhotic portal hypertension, its pathogenesis remains elusive. Insight may be gained from study of early-onset familial idiopathic noncirrhotic portal hypertension, in which Mendelian mutations may account for disease. We performed exome sequencing of eight subjects from six kindreds with onset of portal hypertension of indeterminate etiology during infancy or childhood. Three subjects from two consanguineous families shared the identical rare homozygous p.N46S mutation in DGUOK, a deoxyguanosine kinase required for mitochondrial DNA replication; haplotype sharing demonstrated that the mutation in the two families was inherited from a remote common ancestor. All three affected subjects had stable portal hypertension with noncirrhotic liver disease for 6-16 years of follow-up. This mutation impairs adenosine triphosphate binding and reduces catalytic activity. Loss-of-function mutations in DGUOK have previously been implicated in cirrhosis and liver failure but not in isolated portal hypertension. Interestingly, treatment of patients with human immunodeficiency viral infection with the nucleoside analogue didanosine is known to cause portal hypertension in a subset of patients and lowers deoxyguanosine kinase levels in vitro; the current findings implicate these effects on deoxyguanosine kinase in the causal mechanism.

CONCLUSION: Our findings provide new insight into the mechanisms mediating inherited and acquired noncirrhotic portal hypertension, expand the phenotypic spectrum of DGUOK deficiency, and provide a new genetic test for a specific cause of idiopathic noncirrhotic portal hypertension. (Hepatology 2016;63:1977-1986).

}, keywords = {Adolescent, Amino Acid Sequence, Animals, Cattle, Child, Child, Preschool, DNA Mutational Analysis, Dogs, Female, Genes, Recessive, Homozygote, Humans, Hypertension, Portal, Infant, Liver Failure, Male, Molecular Sequence Data, Pedigree, Phosphotransferases (Alcohol Group Acceptor), Principal Component Analysis, Rats, Young Adult}, issn = {1527-3350}, doi = {10.1002/hep.28499}, author = {Vilarinho, S{\'\i}lvia and Sari, Sinan and Yilmaz, G{\"u}ldal and Stiegler, Amy L and Boggon, Titus J and Jain, Dhanpat and Akyol, G{\"u}len and Dalgi{\c c}, Buket and G{\"u}nel, Murat and Lifton, Richard P} } @article {29, title = {Somatic mosaicism for a lethal TRPV4 mutation results in non-lethal metatropic dysplasia.}, journal = {Am J Med Genet A}, volume = {170}, year = {2016}, month = {2016 Dec}, pages = {3298-3302}, abstract = {

Dominant mutations in TRPV4, which encodes the Transient Receptor Potential Cation Channel Subfamily V Member 4 calcium channel, result in a series of musculoskeletal disorders that include a set of peripheral neuropathies and a broad phenotypic spectrum of skeletal dysplasias. The skeletal phenotypes range from brachyolmia, in which there is scoliosis with mild short stature, through perinatal lethal metatropic dysplasia. We describe a case with phenotypic findings consistent with metatropic dysplasia, but in whom no TRPV4 mutation was detected by Sanger sequence analysis. Exome sequence analysis identified a known lethal metatropic dysplasia mutation, TRPV4 , which was present at lower frequency than would be expected for a heterozygous change. The affected individual was shown to be a somatic mosaic for the mutation, providing an explanation for the milder than expected phenotype. The data illustrate that high-throughput sequencing of genomic DNA can facilitate detection of mosaicism with higher sensitivity than Sanger sequence analysis and identify a new genetic mechanism for metatropic dysplasia. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Alleles, DNA Mutational Analysis, Dwarfism, Exons, Genetic Association Studies, Humans, Infant, Magnetic Resonance Imaging, Mosaicism, Mutation, Osteochondrodysplasias, Phenotype, Physical Examination, Radiography, TRPV Cation Channels}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37942}, author = {Weinstein, Michael M and Kang, Taekyu and Lachman, Ralph S and Bamshad, Michael and Nickerson, Deborah A and Krakow, Deborah and Cohn, Daniel H} } @article {11, title = {Two locus inheritance of non-syndromic midline craniosynostosis via rare and common alleles.}, journal = {Elife}, volume = {5}, year = {2016}, month = {2016 Sep 08}, abstract = {

Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7\%) had damaging de novo or rare transmitted mutations in , an inhibitor of BMP - induced osteoblast differentiation (p<10). mutations nonetheless showed striking incomplete penetrance (<60\%). Genotypes of a common variant near that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases.

}, keywords = {Alleles, Bone Morphogenetic Protein 2, Craniosynostoses, Exome, Genetic Association Studies, Humans, Infant, Mutation, Penetrance, Sequence Analysis, DNA, Smad6 Protein}, issn = {2050-084X}, doi = {10.7554/eLife.20125}, author = {Timberlake, Andrew T and Choi, Jungmin and Zaidi, Samir and Lu, Qiongshi and Nelson-Williams, Carol and Brooks, Eric D and Bilguvar, Kaya and Tikhonova, Irina and Mane, Shrikant and Yang, Jenny F and Sawh-Martinez, Rajendra and Persing, Sarah and Zellner, Elizabeth G and Loring, Erin and Chuang, Carolyn and Galm, Amy and Hashim, Peter W and Steinbacher, Derek M and DiLuna, Michael L and Duncan, Charles C and Pelphrey, Kevin A and Zhao, Hongyu and Persing, John A and Lifton, Richard P} } @article {416, title = {Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes.}, journal = {Am J Med Genet A}, volume = {170}, year = {2016}, month = {2016 11}, pages = {2965-2974}, abstract = {

Visceral motility dysfunction is a key feature of genetic disorders such as megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS, MIM moved from 249210 to 155310), chronic intestinal pseudo-obstruction (CIPO, MIM609629), and multisystemic smooth muscle dysfunction syndrome (MSMDS, MIM613834). The genetic bases of these conditions recently begun to be clarified with the identification of pathogenic variants in ACTG2, ACTA2, and MYH11 in individuals with visceral motility dysfunction. The MMIHS was associated with the heterozygous variant in ACTG2 and homozygous variant in MYH11, while the heterozygous variant in ACTA2 was observed in patients with MSMDS. In this study, we describe the clinical data as well as the molecular investigation of seven individuals with visceral myopathy phenotypes. Five patients presented with MMIHS, including two siblings from consanguineous parents, one had CIPO, and the other had MSMDS. In three individuals with MMIHS and in one with CIPO we identified heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile). In the individual with MSMDS we identified a heterozygous variant in ACTA2. We performed the whole-exome sequencing in one sibling with MMIHS and her parents; however, the pathogenic variant responsible for her phenotype could not be identified. These results reinforce the clinical and genetic heterogeneity of the visceral myopathies. Although many cases of MMIHS are associated with ACTG2 variants, we suggest that other genes, besides MYH11, could cause the MMIHS with autosomal recessive pattern. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Abnormalities, Multiple, Actins, Child, Preschool, Colon, Consanguinity, DNA Mutational Analysis, Fatal Outcome, Female, Genetic Association Studies, Humans, Infant, Infant, Newborn, Intestinal Pseudo-Obstruction, Male, Mutation, Phenotype, Polymorphism, Single Nucleotide, Treatment Outcome, Ultrasonography, Prenatal, Urinary Bladder}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37857}, author = {Moreno, Carolina Araujo and Metze, Konradin and Lomazi, Elizete Aparecida and Bertola, D{\'e}bora Romeo and Barbosa, Ricardo Henrique Almeida and Cosentino, Viviana and Sobreira, Nara and Cavalcanti, Denise Pontes} } @article {641, title = {An anadysplasia-like, spontaneously remitting spondylometaphyseal dysplasia secondary to lamin B receptor (LBR) gene mutations: further definition of the phenotypic heterogeneity of LBR-bone dysplasias.}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Jan}, pages = {159-63}, abstract = {

We describe a boy who has an anadysplasia-like spondylometaphyseal dysplasia. By whole exome sequencing he was shown to have compound heterozygous mutations of LBR that codes for the lamin B receptor. He shares many similarities with a case previously described, but in whom the early natural history could not be established [Borovik et al., 2013]. Thus, in addition to Greenberg dysplasia (a perinatal lethal disorder), homozygosity or compound heterozygosity of mutations in LBR can result in a mild, spontaneously regressing bone dysplasia.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Mutation, Osteochondrodysplasias, Phenotype, Pregnancy, Radiography, Receptors, Cytoplasmic and Nuclear, Spine}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36808}, author = {Sobreira, Nara and Modaff, Peggy and Steel, Gary and You, Jing and Nanda, Sonia and Hoover-Fong, Julie and Valle, David and Pauli, Richard M} } @article {179, title = {Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 May}, pages = {528-34}, abstract = {

Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.

}, keywords = {Animals, Atrophy, Autophagy, Cerebellar Diseases, Cerebellum, Child, Preschool, Female, Gene Frequency, Humans, Infant, Lod Score, Lysosomal Storage Diseases, Lysosomes, Male, Mutation, Phagosomes, Sorting Nexins, Spinocerebellar Ataxias, Syndrome, Zebrafish}, issn = {1546-1718}, doi = {10.1038/ng.3256}, author = {Akizu, Naiara and Cantagrel, Vincent and Zaki, Maha S and Al-Gazali, Lihadh and Wang, Xin and Rosti, Rasim Ozgur and Dikoglu, Esra and Gelot, Antoinette Bernabe and Rosti, Basak and Vaux, Keith K and Scott, Eric M and Silhavy, Jennifer L and Schroth, Jana and Copeland, Brett and Schaffer, Ashleigh E and Gordts, Philip L S M and Esko, Jeffrey D and Buschman, Matthew D and Field, Seth J and Napolitano, Gennaro and Abdel-Salam, Ghada M and Ozgul, R Koksal and Sag{\i}roglu, Mahmut Samil and Azam, Matloob and Ismail, Samira and Aglan, Mona and Selim, Laila and Mahmoud, Iman G and Abdel-Hadi, Sawsan and Badawy, Amera El and Sadek, Abdelrahim A and Mojahedi, Faezeh and Kayserili, H{\"u}lya and Masri, Amira and Bastaki, Laila and Temtamy, Samia and M{\"u}ller, Ulrich and Desguerre, Isabelle and Casanova, Jean-Laurent and Dursun, Ali and G{\"u}nel, Murat and Gabriel, Stacey B and de Lonlay, Pascale and Gleeson, Joseph G} } @article {640, title = {Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome.}, journal = {Clin J Am Soc Nephrol}, volume = {10}, year = {2015}, month = {2015 Jun 05}, pages = {1011-9}, abstract = {

BACKGROUND AND OBJECTIVES: Genetic and acquired abnormalities causing dysregulation of the complement alternative pathway contribute to atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute kidney failure. However, in a substantial proportion of patients the disease-associated alterations are still unknown.

DESIGN, SETTING, PARTICIPANTS, \& MEASUREMENTS: Whole-exome and whole-genome sequencing were performed in two unrelated families with infantile recessive aHUS. Sequencing of cDNA from affected individuals was used to test for the presence of aberrant mRNA species. Expression of mutant diacylglycerol kinase epsilon (DGKE) protein was evaluated with western blotting.

RESULTS: Whole-exome sequencing analysis with conventional variant filtering parameters did not reveal any obvious candidate mutation in the first family. The report of aHUS-associated mutations in DGKE, encoding DGKE, led to re-examination of the noncoding DGKE variants obtained from next-generation sequencing, allowing identification of a novel intronic DGKE mutation (c.888+40A>G) that segregated with disease. Sequencing of cDNA from affected individuals revealed aberrant forms of DGKE mRNA predicted to cause profound abnormalities in the protein catalytic site. By whole-genome sequencing, the same mutation was found in compound heterozygosity with a second nonsense DGKE mutation in all affected siblings of another unrelated family. Homozygous and compound heterozygous patients presented similar clinical features, including aHUS presentation in the first year of life, multiple relapsing episodes, and proteinuria, which are prototypical of DGKE-associated aHUS.

CONCLUSIONS: This is the first report of a mutation located beyond the exon-intron boundaries in aHUS. Intronic mutations such as these are underreported because conventional filtering parameters used to process next-generation sequencing data routinely exclude these regions from downstream analyses in both research and clinical settings. The results suggest that analysis of noncoding regions of aHUS-associated genes coupled with mRNA sequencing might provide a tool to explain genetically unsolved aHUS cases.

}, keywords = {Adolescent, Atypical Hemolytic Uremic Syndrome, Base Sequence, Blotting, Western, Child, Diacylglycerol Kinase, DNA Mutational Analysis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Infant, Introns, Male, Molecular Sequence Data, Mutation, Phenotype, Predictive Value of Tests, Risk Factors}, issn = {1555-905X}, doi = {10.2215/CJN.08520814}, author = {Mele, Caterina and Lemaire, Mathieu and Iatropoulos, Paraskevas and Piras, Rossella and Bresin, Elena and Bettoni, Serena and Bick, David and Helbling, Daniel and Veith, Regan and Valoti, Elisabetta and Donadelli, Roberta and Murer, Luisa and Neunh{\"a}userer, Maria and Breno, Matteo and Fremeaux-Bacchi, Veronique and Lifton, Richard and Remuzzi, Giuseppe and Noris, Marina} } @article {153, title = {Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism.}, journal = {J Med Genet}, volume = {52}, year = {2015}, month = {2015 Sep}, pages = {612-6}, abstract = {

BACKGROUND: Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20-30\%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus.

METHODS: Clinical and functional characterisation of a novel homozygous intronic mutation (c.187+241G>A) in the insulin gene in a child identified through the Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu).

RESULTS: The proband had insulin-requiring diabetes from birth. Ultrasonography revealed a structurally normal pancreas and C-peptide was undetectable despite readily detectable amylin, suggesting the presence of dysfunctional β cells. Whole-exome sequencing revealed the novel mutation. In silico analysis predicted a mutant mRNA product resulting from preferential recognition of a newly created splice site. Wild-type and mutant human insulin gene constructs were derived and transiently expressed in INS-1 cells. We confirmed the predicted transcript and found an additional transcript created via an ectopic splice acceptor site.

CONCLUSIONS: Dominant INS mutations cause diabetes via a mutated translational product causing endoplasmic reticulum stress. We describe a novel mechanism of diabetes, without β cell death, due to creation of two unstable mutant transcripts predicted to undergo nonsense and non-stop-mediated decay, respectively. Our discovery may have broader implications for those with insulin deficiency later in life.

}, keywords = {Diabetes Mellitus, Humans, Infant, Insulin, Regular, Human, Introns, Mutation, Sequence Analysis, DNA}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2015-103220}, author = {Carmody, David and Park, Soo-Young and Ye, Honggang and Perrone, Marie E and Alkorta-Aranburu, G and Highland, Heather M and Hanis, Craig L and Philipson, Louis H and Bell, Graeme I and Greeley, Siri Atma W} } @article {173, title = {COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Jun}, pages = {654-60}, abstract = {

Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.

}, keywords = {Amino Acid Sequence, Arthritis, Autoimmune Diseases, Child, Preschool, Coatomer Protein, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Female, Genetic Association Studies, Genetic Predisposition to Disease, Golgi Apparatus, HEK293 Cells, Humans, Infant, Lod Score, Lung Diseases, Interstitial, Male, Molecular Sequence Data, Pedigree, Protein Transport}, issn = {1546-1718}, doi = {10.1038/ng.3279}, author = {Watkin, Levi B and Jessen, Birthe and Wiszniewski, Wojciech and Vece, Timothy J and Jan, Max and Sha, Youbao and Thamsen, Maike and Santos-Cortez, Regie L P and Lee, Kwanghyuk and Gambin, Tomasz and Forbes, Lisa R and Law, Christopher S and Stray-Pedersen, Asbj{\o}rg and Cheng, Mickie H and Mace, Emily M and Anderson, Mark S and Liu, Dongfang and Tang, Ling Fung and Nicholas, Sarah K and Nahmod, Karen and Makedonas, George and Canter, Debra L and Kwok, Pui-Yan and Hicks, John and Jones, Kirk D and Penney, Samantha and Jhangiani, Shalini N and Rosenblum, Michael D and Dell, Sharon D and Waterfield, Michael R and Papa, Feroz R and Muzny, Donna M and Zaitlen, Noah and Leal, Suzanne M and Gonzaga-Jauregui, Claudia and Boerwinkle, Eric and Eissa, N Tony and Gibbs, Richard A and Lupski, James R and Orange, Jordan S and Shum, Anthony K} } @article {194, title = {De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay.}, journal = {Am J Hum Genet}, volume = {96}, year = {2015}, month = {2015 Mar 05}, pages = {462-73}, abstract = {

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).

}, keywords = {Arthrogryposis, Contracture, Craniofacial Dysostosis, Cytoskeletal Proteins, Exome, Extremities, Face, Female, Gene Frequency, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Infant, Male, Muscle Hypotonia, Mutation, Missense, Sodium Channels}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.01.003}, author = {Chong, Jessica X and McMillin, Margaret J and Shively, Kathryn M and Beck, Anita E and Marvin, Colby T and Armenteros, Jose R and Buckingham, Kati J and Nkinsi, Naomi T and Boyle, Evan A and Berry, Margaret N and Bocian, Maureen and Foulds, Nicola and Uzielli, Maria Luisa Giovannucci and Haldeman-Englert, Chad and Hennekam, Raoul C M and Kaplan, Paige and Kline, Antonie D and Mercer, Catherine L and Nowaczyk, Malgorzata J M and Klein Wassink-Ruiter, Jolien S and McPherson, Elizabeth W and Moreno, Regina A and Scheuerle, Angela E and Shashi, Vandana and Stevens, Cathy A and Carey, John C and Monteil, Arnaud and Lory, Philippe and Tabor, Holly K and Smith, Joshua D and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} } @article {215, title = {Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.}, journal = {Blood}, volume = {125}, year = {2015}, month = {2015 Jan 22}, pages = {591-9}, abstract = {

Germline loss-of-function mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) cause immunodeficiency, whereas somatic gain-of-function mutations in STAT3 are associated with large granular lymphocytic leukemic, myelodysplastic syndrome, and aplastic anemia. Recently, germline mutations in STAT3 have also been associated with autoimmune disease. Here, we report on 13 individuals from 10 families with lymphoproliferation and early-onset solid-organ autoimmunity associated with 9 different germline heterozygous mutations in STAT3. Patients exhibited a variety of clinical features, with most having lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity (lung, gastrointestinal, hepatic, and/or endocrine dysfunction), infections, and short stature. Functional analyses demonstrate that these mutations confer a gain-of-function in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Treatment targeting a cytokine pathway that signals through STAT3 led to clinical improvement in 1 patient, suggesting a potential therapeutic option for such patients. These results suggest that there is a broad range of autoimmunity caused by germline STAT3 gain-of-function mutations, and that hematologic autoimmunity is a major component of this newly described disorder. Some patients for this study were enrolled in a trial registered at www.clinicaltrials.gov as $\#$NCT00001350.

}, keywords = {Adolescent, Adult, Autoimmune Diseases, Child, Child, Preschool, Female, Genetic Diseases, Inborn, Humans, Infant, Lymphoproliferative Disorders, Male, Mutation, Phosphorylation, STAT1 Transcription Factor, STAT3 Transcription Factor, STAT5 Transcription Factor, T-Lymphocytes, Regulatory}, issn = {1528-0020}, doi = {10.1182/blood-2014-09-602763}, author = {Milner, Joshua D and Vogel, Tiphanie P and Forbes, Lisa and Ma, Chi A and Stray-Pedersen, Asbj{\o}rg and Niemela, Julie E and Lyons, Jonathan J and Engelhardt, Karin R and Zhang, Yu and Topcagic, Nermina and Roberson, Elisha D O and Matthews, Helen and Verbsky, James W and Dasu, Trivikram and Vargas-Hernandez, Alexander and Varghese, Nidhy and McClain, Kenneth L and Karam, Lina B and Nahmod, Karen and Makedonas, George and Mace, Emily M and Sorte, Hanne S and Perminow, G{\o}ri and Rao, V Koneti and O{\textquoteright}Connell, Michael P and Price, Susan and Su, Helen C and Butrick, Morgan and McElwee, Joshua and Hughes, Jason D and Willet, Joseph and Swan, David and Xu, Yaobo and Santibanez-Koref, Mauro and Slowik, Voytek and Dinwiddie, Darrell L and Ciaccio, Christina E and Saunders, Carol J and Septer, Seth and Kingsmore, Stephen F and White, Andrew J and Cant, Andrew J and Hambleton, Sophie and Cooper, Megan A} } @article {198, title = {Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes.}, journal = {J Clin Invest}, volume = {125}, year = {2015}, month = {2015 Feb}, pages = {636-51}, abstract = {

Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65\% of patients harbor mutations in genes that encode subunits or regulators of the cohesin complex, including NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A (KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" rather than cohesinopathies.

}, keywords = {Adolescent, Adult, Cell Cycle Proteins, Child, Child, Preschool, Chondroitin Sulfate Proteoglycans, Chromosomal Proteins, Non-Histone, Codon, Nonsense, De Lange Syndrome, Exome, Exonucleases, Gene Expression Profiling, Gene Expression Regulation, Genome-Wide Association Study, Heterozygote, Histone Deacetylases, Histone-Lysine N-Methyltransferase, Humans, Infant, Male, Myeloid-Lymphoid Leukemia Protein, Phenotype, Proteins, Repressor Proteins, Transcriptome}, issn = {1558-8238}, doi = {10.1172/JCI77435}, author = {Yuan, Bo and Pehlivan, Davut and Karaca, Ender and Patel, Nisha and Charng, Wu-Lin and Gambin, Tomasz and Gonzaga-Jauregui, Claudia and Sutton, V Reid and Yesil, G{\"o}zde and Bozdogan, Sevcan Tug and Tos, Tulay and Koparir, Asuman and Koparir, Erkan and Beck, Christine R and Gu, Shen and Aslan, Huseyin and Yuregir, Ozge Ozalp and Al Rubeaan, Khalid and Alnaqeb, Dhekra and Alshammari, Muneera J and Bayram, Yavuz and Atik, Mehmed M and Aydin, Hatip and Geckinli, B Bilge and Seven, Mehmet and Ulucan, Hakan and Fenercioglu, Elif and Ozen, Mustafa and Jhangiani, Shalini and Muzny, Donna M and Boerwinkle, Eric and Tuysuz, Beyhan and Alkuraya, Fowzan S and Gibbs, Richard A and Lupski, James R} } @article {161, title = {Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Jul}, pages = {809-13}, abstract = {

Docosahexanoic acid (DHA) is the most abundant omega-3 fatty acid in brain, and, although it is considered essential, deficiency has not been linked to disease. Despite the large mass of DHA in phospholipids, the brain does not synthesize it. DHA is imported across the blood-brain barrier (BBB) through the major facilitator superfamily domain-containing 2a (MFSD2A) protein. MFSD2A transports DHA as well as other fatty acids in the form of lysophosphatidylcholine (LPC). We identify two families displaying MFSD2A mutations in conserved residues. Affected individuals exhibited a lethal microcephaly syndrome linked to inadequate uptake of LPC lipids. The MFSD2A mutations impaired transport activity in a cell-based assay. Moreover, when expressed in mfsd2aa-morphant zebrafish, mutants failed to rescue microcephaly, BBB breakdown and lethality. Our results establish a link between transport of DHA and LPCs by MFSD2A and human brain growth and function, presenting the first evidence of monogenic disease related to transport of DHA in humans.

}, keywords = {Adolescent, Animals, Biological Transport, Blood-Brain Barrier, Brain, Case-Control Studies, Child, Child, Preschool, Consanguinity, Fatty Acids, Omega-3, Female, Genes, Lethal, Genetic Association Studies, HEK293 Cells, Humans, Infant, Male, Mice, Knockout, Microcephaly, Mutation, Missense, Syndrome, Tumor Suppressor Proteins, Zebrafish}, issn = {1546-1718}, doi = {10.1038/ng.3311}, author = {Guemez-Gamboa, Alicia and Nguyen, Long N and Yang, Hongbo and Zaki, Maha S and Kara, Majdi and Ben-Omran, Tawfeg and Akizu, Naiara and Rosti, Rasim Ozgur and Rosti, Basak and Scott, Eric and Schroth, Jana and Copeland, Brett and Vaux, Keith K and Cazenave-Gassiot, Amaury and Quek, Debra Q Y and Wong, Bernice H and Tan, Bryan C and Wenk, Markus R and G{\"u}nel, Murat and Gabriel, Stacey and Chi, Neil C and Silver, David L and Gleeson, Joseph G} } @article {237, title = {Mutations in COL27A1 cause Steel syndrome and suggest a founder mutation effect in the Puerto Rican population.}, journal = {Eur J Hum Genet}, volume = {23}, year = {2015}, month = {2015 Mar}, pages = {342-6}, abstract = {

Osteochondrodysplasias represent a large group of developmental structural disorders that can be caused by mutations in a variety of genes responsible for chondrocyte development, differentiation, mineralization and early ossification. The application of whole-exome sequencing to disorders apparently segregating as Mendelian traits has proven to be an effective approach to disease gene identification for conditions with unknown molecular etiology. We identified a homozygous missense variant p.(Gly697Arg) in COL27A1, in a family with Steel syndrome and no consanguinity. Interestingly, the identified variant seems to have arisen as a founder mutation in the Puerto Rican population.

}, keywords = {Amino Acid Sequence, Child, Preschool, Comparative Genomic Hybridization, Exome, Female, Fibrillar Collagens, Follow-Up Studies, Founder Effect, Genotype, Hispanic Americans, Humans, Infant, Male, Molecular Sequence Data, Mutation, Osteochondrodysplasias, Pedigree, Polymorphism, Single Nucleotide, Prostaglandins F, Puerto Rico, Sequence Alignment}, issn = {1476-5438}, doi = {10.1038/ejhg.2014.107}, author = {Gonzaga-Jauregui, Claudia and Gamble, Candace N and Yuan, Bo and Penney, Samantha and Jhangiani, Shalini and Muzny, Donna M and Gibbs, Richard A and Lupski, James R and Hecht, Jacqueline T} } @article {109, title = {Mutations in Either TUBB or MAPRE2 Cause Circumferential Skin Creases Kunze Type.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Dec 03}, pages = {790-800}, abstract = {

Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a β-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone-dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect.

}, keywords = {Adolescent, Animals, Brain, Child, Cutis Laxa, Female, Gene Dosage, Gene Expression Regulation, Developmental, Genes, Recessive, Hamartoma, Haploinsufficiency, Humans, Infant, Inheritance Patterns, Male, Microtubule-Associated Proteins, Microtubules, Mutation, Protein Folding, Protein Multimerization, Skin, Skin Abnormalities, Tubulin, Young Adult, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.10.014}, author = {Isrie, Mala and Breuss, Martin and Tian, Guoling and Hansen, Andi Harley and Cristofoli, Francesca and Morandell, Jasmin and Kupchinsky, Zachari A and Sifrim, Alejandro and Rodriguez-Rodriguez, Celia Maria and Dapena, Elena Porta and Doonanco, Kurston and Leonard, Norma and Tinsa, Faten and Moortgat, St{\'e}phanie and Ulucan, Hakan and Koparir, Erkan and Karaca, Ender and Katsanis, Nicholas and Marton, Valeria and Vermeesch, Joris Robert and Davis, Erica E and Cowan, Nicholas J and Keays, David Anthony and Van Esch, Hilde} } @article {120, title = {Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Nov 05}, pages = {691-707}, abstract = {

The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. The LCRs flanking a contiguous genomic interval encompassing both RAI1 and PMP22 do not share extensive homology; thus, duplications encompassing both loci are rare and potentially generated by a different mutational mechanism. We characterized genomic rearrangements that simultaneously duplicate PMP22 and RAI1, including nine potential complex genomic rearrangements, in 23 subjects by high-resolution array comparative genomic hybridization and breakpoint junction sequencing. Insertions and microhomologies were found at the breakpoint junctions, suggesting potential replicative mechanisms for rearrangement formation. At the breakpoint junctions of these nonrecurrent rearrangements, enrichment of repetitive DNA sequences was observed, indicating that they might predispose to genomic instability and rearrangement. Clinical evaluation revealed blended PTLS and CMT1A phenotypes with a potential earlier onset of neuropathy. Moreover, additional clinical findings might be observed due to the extra duplicated material included in the rearrangements. Our genomic analysis suggests replicative mechanisms as a predominant mechanism underlying PMP22-RAI1 contiguous gene duplications and provides further evidence supporting the role of complex genomic architecture in genomic instability.

}, keywords = {Abnormalities, Multiple, Charcot-Marie-Tooth Disease, Child, Child, Preschool, Chromosome Disorders, Chromosome Duplication, Chromosomes, Human, Pair 17, Comparative Genomic Hybridization, Female, Follow-Up Studies, Gene Duplication, Gene Rearrangement, Genome, Human, Genomics, Humans, Infant, Male, Models, Genetic, Myelin Proteins, Phenotype, Prognosis, Recombination, Genetic, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.10.003}, author = {Yuan, Bo and Harel, Tamar and Gu, Shen and Liu, Pengfei and Burglen, Lydie and Chantot-Bastaraud, Sandra and Gelowani, Violet and Beck, Christine R and Carvalho, Claudia M B and Cheung, Sau Wai and Coe, Andrew and Malan, Val{\'e}rie and Munnich, Arnold and Magoulas, Pilar L and Potocki, Lorraine and Lupski, James R} } @article {171, title = {Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism.}, journal = {Elife}, volume = {4}, year = {2015}, month = {2015 Apr 24}, pages = {e06315}, abstract = {

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5\%) shared the identical, previously unidentified, heterozygous CACNA1H(M1549V) mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1H(M1549V) showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca(2+), the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.

}, keywords = {Adolescent, Adult, Age of Onset, Aldosterone, Amino Acid Sequence, Calcium, Calcium Channels, T-Type, Calcium Signaling, Child, Child, Preschool, Female, Gene Expression, Genotype, Heterozygote, Humans, Hyperaldosteronism, Hypertension, Infant, Male, Membrane Potentials, Middle Aged, Molecular Sequence Data, Mutation, Phenotype, Recurrence, Sequence Alignment, Zona Glomerulosa}, issn = {2050-084X}, doi = {10.7554/eLife.06315}, author = {Scholl, Ute I and St{\"o}lting, Gabriel and Nelson-Williams, Carol and Vichot, Alfred A and Choi, Murim and Loring, Erin and Prasad, Manju L and Goh, Gerald and Carling, Tobias and Juhlin, C Christofer and Quack, Ivo and Rump, Lars C and Thiel, Anne and Lande, Marc and Frazier, Britney G and Rasoulpour, Majid and Bowlin, David L and Sethna, Christine B and Trachtman, Howard and Fahlke, Christoph and Lifton, Richard P} } @article {190, title = {Somatic Activating RAS Mutations Cause Vascular Tumors Including Pyogenic Granuloma.}, journal = {J Invest Dermatol}, volume = {135}, year = {2015}, month = {2015 Jun}, pages = {1698-1700}, keywords = {Adolescent, Cell Proliferation, Child, Child, Preschool, Female, Gene Expression Regulation, Neoplastic, Granuloma, Pyogenic, Humans, Infant, Infant, Newborn, Male, Mutation, ras Proteins, Vascular Neoplasms}, issn = {1523-1747}, doi = {10.1038/jid.2015.55}, author = {Lim, Young H and Douglas, Stephanie R and Ko, Christine J and Antaya, Richard J and McNiff, Jennifer M and Zhou, Jing and Choate, Keith A and Narayan, Deepak} } @article {158, title = {Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh{\textquoteright}s disease.}, journal = {Mol Genet Metab}, volume = {115}, year = {2015}, month = {2015 Aug}, pages = {161-7}, abstract = {

PURPOSE: 3-Hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare disorder of valine metabolism. We present a family with the oldest reported subjects with HIBCH deficiency and provide support that HIBCH deficiency should be included in the differential for elevated hydroxy-C4-carnitine in newborn screening (NBS).

METHODS: Whole exome sequencing (WES) was performed on one affected sibling. HIBCH enzymatic activity was measured in patient fibroblasts. Acylcarnitines were measured by electrospray ionization tandem mass spectrometry (ESI-MS/MS). Disease incidence was estimated using a cohort of 61,434 individuals.

RESULTS: Two siblings presented with infantile-onset, progressive neurodegenerative disease. WES identified a novel homozygous variant in HIBCH c.196C>T; p.Arg66Trp. HIBCH enzymatic activity was significantly reduced in patients{\textquoteright} fibroblasts. Acylcarnitine analysis showed elevated hydroxy-C4-carnitine in blood spots of both affected siblings, including in their NBS cards, while plasma acylcarnitines were normal. Estimates show HIBCH deficiency incidence as high as 1 in ~130,000 individuals.

CONCLUSION: We describe a novel family with HIBCH deficiency at the biochemical, enzymatic and molecular level. Disease incidence estimates indicate HIBCH deficiency may be under-diagnosed. This together with the elevated hydroxy-C4-carnitine found in the retrospective analysis of our patient{\textquoteright}s NBS cards suggests that this disorder could be screened for by NBS programs and should be added to the differential diagnosis for elevated hydroxy-C4-carnitine which is already measured in most NBS programs using MS/MS.

}, keywords = {Abnormalities, Multiple, Adolescent, Amino Acid Metabolism, Inborn Errors, Carnitine, Child, Child, Preschool, Cohort Studies, Exome, Female, Fibroblasts, Humans, Infant, Infant, Newborn, Leigh Disease, Male, Mass Spectrometry, Neonatal Screening, Prognosis, Retrospective Studies, Sequence Analysis, DNA, Siblings, Thiolester Hydrolases}, issn = {1096-7206}, doi = {10.1016/j.ymgme.2015.05.008}, author = {Stiles, Ashlee R and Ferdinandusse, Sacha and Besse, Arnaud and Appadurai, Vivek and Leydiker, Karen B and Cambray-Forker, E J and Bonnen, Penelope E and Abdenur, Jose E} } @article {189, title = {X-linked acrogigantism syndrome: clinical profile and therapeutic responses.}, journal = {Endocr Relat Cancer}, volume = {22}, year = {2015}, month = {2015 Jun}, pages = {353-67}, abstract = {

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

}, keywords = {Acromegaly, Adenoma, Adolescent, Child, Child, Preschool, Chromosomes, Human, X, Female, Gigantism, Humans, Infant, Male, Pituitary Neoplasms, Young Adult}, issn = {1479-6821}, doi = {10.1530/ERC-15-0038}, author = {Beckers, Albert and Lodish, Maya Beth and Trivellin, Giampaolo and Rostomyan, Liliya and Lee, Misu and Faucz, Fabio R and Yuan, Bo and Choong, Catherine S and Caberg, Jean-Hubert and Verrua, Elisa and Naves, Luciana Ansaneli and Cheetham, Tim D and Young, Jacques and Lysy, Philippe A and Petrossians, Patrick and Cotterill, Andrew and Shah, Nalini Samir and Metzger, Daniel and Castermans, Emilie and Ambrosio, Maria Rosaria and Villa, Chiara and Strebkova, Natalia and Mazerkina, Nadia and Gaillard, St{\'e}phan and Barra, Gustavo Barcelos and Casulari, Luis Augusto and Neggers, Sebastian J and Salvatori, Roberto and Jaffrain-Rea, Marie-Lise and Zacharin, Margaret and Santamaria, Beatriz Lecumberri and Zacharieva, Sabina and Lim, Ee Mun and Mantovani, Giovanna and Zatelli, Maria Chaira and Collins, Michael T and Bonneville, Jean-Fran{\c c}ois and Quezado, Martha and Chittiboina, Prashant and Oldfield, Edward H and Bours, Vincent and Liu, Pengfei and W de Herder, Wouter and Pellegata, Natalia and Lupski, James R and Daly, Adrian F and Stratakis, Constantine A} } @article {248, title = {De novo truncating mutations in AHDC1 in individuals with syndromic expressive language delay, hypotonia, and sleep apnea.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 May 01}, pages = {784-9}, abstract = {

Clinical whole-exome sequencing (WES) for identification of mutations leading to Mendelian disease has been offered to the medical community since 2011. Clinically undiagnosed neurological disorders are the most frequent basis for test referral, and currently, approximately 25\% of such cases are diagnosed at the molecular level. To date, there are approximately 4,000 "known" disease-associated loci, and many are associated with striking dysmorphic features, making genotype-phenotype correlations relatively straightforward. A significant fraction of cases, however, lack characteristic dysmorphism or clinical pathognomonic traits and are dependent upon molecular tests for definitive diagnoses. Further, many molecular diagnoses are guided by recent gene-disease association discoveries. Hence, there is a critical interplay between clinical testing and research leading to gene-disease association discovery. Here, we describe four probands, all of whom presented with hypotonia, intellectual disability, global developmental delay, and mildly dysmorphic facial features. Three of the four also had sleep apnea. Each was a simplex case without a remarkable family history. Using WES, we identified AHDC1 de novo truncating mutations that most likely cause this genetic syndrome.

}, keywords = {Child, Child, Preschool, DNA-Binding Proteins, Exome, Female, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Muscle Hypotonia, Mutation, Sleep Apnea Syndromes, Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.04.006}, author = {Xia, Fan and Bainbridge, Matthew N and Tan, Tiong Yang and Wangler, Michael F and Scheuerle, Angela E and Zackai, Elaine H and Harr, Margaret H and Sutton, V Reid and Nalam, Roopa L and Zhu, Wenmiao and Nash, Margot and Ryan, Monique M and Yaplito-Lee, Joy and Hunter, Jill V and Deardorff, Matthew A and Penney, Samantha J and Beaudet, Arthur L and Plon, Sharon E and Boerwinkle, Eric A and Lupski, James R and Eng, Christine M and Muzny, Donna M and Yang, Yaping and Gibbs, Richard A} } @article {240, title = {Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Sep}, pages = {2240-9}, abstract = {

Patients with physical findings suggestive of Treacher Collins syndrome (TCS) or mandibulofacial dysostosis (MFD) and macrocytic anemia diagnostic of Diamond-Blackfan anemia (DBA) have been reported. Disease-causing genes have been identified for TCS and other MFDs. Mutations in several ribosomal protein genes and the transcription factor GATA1 result in DBA. However, no disease-causing mutation had been identified in the reported patients with the combination of TCS/MFD and DBA phenotype, and we hypothesized that pathogenic mutations in a single gene could be identified using whole exome analysis. We studied probands from six unrelated families. Combining exome analysis and Sanger sequencing, we identified likely pathogenic mutations in 5/6 families. Two mutations in unrelated families were seen in RPS26, the known DBA10 gene. One variant was predicted to affect mRNA splicing, and the other to lead to protein truncation. In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26. De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene. We conclude that the phenotype combining features of TCS with DBA is genetically heterogeneous. Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth. The phenotype combining TCS/MFD and DBA is highly variable, overlaps with DBA and lies within the phenotypic spectrum of ribosomopathies. {\textcopyright} 2014 Wiley Periodicals, Inc.

}, keywords = {Adult, Anemia, Diamond-Blackfan, Apoptosis Regulatory Proteins, Child, Preschool, Exome, Family, Female, Genetic Heterogeneity, Humans, Infant, Infant, Newborn, Male, Mandibulofacial Dysostosis, Pedigree, Phenotype, Pregnancy, Ribosomal Proteins, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36633}, author = {Gripp, Karen W and Curry, Cynthia and Olney, Ann Haskins and Sandoval, Claudio and Fisher, Jamie and Chong, Jessica Xiao-Ling and Pilchman, Lisa and Sahraoui, Rebecca and Stabley, Deborah L and Sol-Church, Katia} } @article {281, title = {The genetic basis of DOORS syndrome: an exome-sequencing study.}, journal = {Lancet Neurol}, volume = {13}, year = {2014}, month = {2014 Jan}, pages = {44-58}, abstract = {

BACKGROUND: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.

METHODS: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR.

FINDINGS: 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis.

INTERPRETATION: Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24.

FUNDING: US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.

}, keywords = {Adolescent, Carrier Proteins, Child, Child, Preschool, Craniofacial Abnormalities, Exome, Female, Hand Deformities, Congenital, Hearing Loss, Sensorineural, Humans, Infant, Intellectual Disability, Internationality, Male, Nails, Malformed, Phenotype, Sequence Analysis, DNA, Young Adult}, issn = {1474-4465}, doi = {10.1016/S1474-4422(13)70265-5}, author = {Campeau, Philippe M and Kasperaviciute, Dalia and Lu, James T and Burrage, Lindsay C and Kim, Choel and Hori, Mutsuki and Powell, Berkley R and Stewart, Fiona and F{\'e}lix, T{\^e}mis Maria and van den Ende, Jenneke and Wisniewska, Marzena and Kayserili, H{\"u}lya and Rump, Patrick and Nampoothiri, Sheela and Aftimos, Salim and Mey, Antje and Nair, Lal D V and Begleiter, Michael L and De Bie, Isabelle and Meenakshi, Girish and Murray, Mitzi L and Repetto, Gabriela M and Golabi, Mahin and Blair, Edward and Male, Alison and Giuliano, Fabienne and Kariminejad, Ariana and Newman, William G and Bhaskar, Sanjeev S and Dickerson, Jonathan E and Kerr, Bronwyn and Banka, Siddharth and Giltay, Jacques C and Wieczorek, Dagmar and Tostevin, Anna and Wiszniewska, Joanna and Cheung, Sau Wai and Hennekam, Raoul C and Gibbs, Richard A and Lee, Brendan H and Sisodiya, Sanjay M} } @article {234, title = {Germ-line and somatic DICER1 mutations in pineoblastoma.}, journal = {Acta Neuropathol}, volume = {128}, year = {2014}, month = {2014 Oct}, pages = {583-95}, abstract = {

Germ-line RB-1 mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line DICER1 mutation in a child with a PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of DICER1 mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for DICER1 mutations; three patients were known carriers of germ-line DICER1 mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify DICER1 mutations in blood gDNA and/or tumour gDNA. Testing for somatic DICER1 mutations was also conducted on one case with a known germ-line DICER1 mutation. From the eighteen PinBs, we identified four deleterious DICER1 mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic DICER1 RNase IIIb mutations were identified. One PinB arising in a germ-line DICER1 mutation carrier was found to have LOH. This study suggests that germ-line DICER1 mutations make a clinically significant contribution to PinB, establishing DICER1 as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line DICER1 mutation. The means by which the second allele is inactivated may differ from other DICER1-related tumours.

}, keywords = {Adolescent, Brain Neoplasms, Child, Child, Preschool, DEAD-box RNA Helicases, DNA Mutational Analysis, Family Health, Female, Germ-Line Mutation, Humans, Infant, Male, Pineal Gland, Pinealoma, Ribonuclease III, Young Adult}, issn = {1432-0533}, doi = {10.1007/s00401-014-1318-7}, author = {de Kock, Leanne and Sabbaghian, Nelly and Druker, Harriet and Weber, Evan and Hamel, Nancy and Miller, Suzanne and Choong, Catherine S and Gottardo, Nicholas G and Kees, Ursula R and Rednam, Surya P and van Hest, Liselotte P and Jongmans, Marjolijn C and Jhangiani, Shalini and Lupski, James R and Zacharin, Margaret and Bouron-Dal Soglio, Doroth{\'e}e and Huang, Annie and Priest, John R and Perry, Arie and Mueller, Sabine and Albrecht, Steffen and Malkin, David and Grundy, Richard G and Foulkes, William D} } @article {207, title = {Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.}, journal = {N Engl J Med}, volume = {371}, year = {2014}, month = {2014 Dec 18}, pages = {2363-74}, abstract = {

BACKGROUND: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood.

METHODS: We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly.

RESULTS: We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients{\textquoteright} pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells.

CONCLUSIONS: We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

}, keywords = {Acromegaly, Adolescent, Adult, Age of Onset, Child, Child, Preschool, Chromosome Duplication, Chromosomes, Human, X, Female, Gigantism, Human Growth Hormone, Humans, Infant, Male, Mutation, Phenotype, Protein Conformation, Receptors, G-Protein-Coupled}, issn = {1533-4406}, doi = {10.1056/NEJMoa1408028}, author = {Trivellin, Giampaolo and Daly, Adrian F and Faucz, Fabio R and Yuan, Bo and Rostomyan, Liliya and Larco, Darwin O and Schernthaner-Reiter, Marie Helene and Szarek, Eva and Leal, Let{\'\i}cia F and Caberg, Jean-Hubert and Castermans, Emilie and Villa, Chiara and Dimopoulos, Aggeliki and Chittiboina, Prashant and Xekouki, Paraskevi and Shah, Nalini and Metzger, Daniel and Lysy, Philippe A and Ferrante, Emanuele and Strebkova, Natalia and Mazerkina, Nadia and Zatelli, Maria Chiara and Lodish, Maya and Horvath, Anelia and de Alexandre, Rodrigo Bertollo and Manning, Allison D and Levy, Isaac and Keil, Margaret F and Sierra, Maria de la Luz and Palmeira, Leonor and Coppieters, Wouter and Georges, Michel and Naves, Luciana A and Jamar, Mauricette and Bours, Vincent and Wu, T John and Choong, Catherine S and Bertherat, Jerome and Chanson, Philippe and Kamenick{\'y}, Peter and Farrell, William E and Barlier, Anne and Quezado, Martha and Bjelobaba, Ivana and Stojilkovic, Stanko S and Wess, Jurgen and Costanzi, Stefano and Liu, Pengfei and Lupski, James R and Beckers, Albert and Stratakis, Constantine A} } @article {253, title = {Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function.}, journal = {Cell}, volume = {157}, year = {2014}, month = {2014 Apr 24}, pages = {636-50}, abstract = {

CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis, and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis.

}, keywords = {Abnormalities, Multiple, Animals, Central Nervous System Diseases, Cerebrum, Child, Preschool, Endoribonucleases, Female, Fibroblasts, Humans, Infant, Male, Mice, Mice, Inbred CBA, Microcephaly, Mutation, Missense, Nuclear Proteins, Peripheral Nervous System Diseases, Phosphotransferases, RNA, Transfer, Transcription Factors}, issn = {1097-4172}, doi = {10.1016/j.cell.2014.02.058}, author = {Karaca, Ender and Weitzer, Stefan and Pehlivan, Davut and Shiraishi, Hiroshi and Gogakos, Tasos and Hanada, Toshikatsu and Jhangiani, Shalini N and Wiszniewski, Wojciech and Withers, Marjorie and Campbell, Ian M and Erdin, Serkan and Isikay, Sedat and Franco, Luis M and Gonzaga-Jauregui, Claudia and Gambin, Tomasz and Gelowani, Violet and Hunter, Jill V and Yesil, G{\"o}zde and Koparir, Erkan and Yilmaz, Sarenur and Brown, Miguel and Briskin, Daniel and Hafner, Markus and Morozov, Pavel and Farazi, Thalia A and Bernreuther, Christian and Glatzel, Markus and Trattnig, Siegfried and Friske, Joachim and Kronnerwetter, Claudia and Bainbridge, Matthew N and Gezdirici, Alper and Seven, Mehmet and Muzny, Donna M and Boerwinkle, Eric and Ozen, Mustafa and Clausen, Tim and Tuschl, Thomas and Yuksel, Adnan and Hess, Andreas and Gibbs, Richard A and Martinez, Javier and Penninger, Josef M and Lupski, James R} } @article {262, title = {Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy.}, journal = {Chest}, volume = {146}, year = {2014}, month = {2014 Nov}, pages = {1176-1186}, abstract = {

BACKGROUND: Motile cilia dysfunction causes primary ciliary dyskinesia (PCD), situs inversus totalis (SI), and a spectrum of laterality defects, yet the prevalence of laterality defects other than SI in PCD has not been prospectively studied.

METHODS: In this prospective study, participants with suspected PCD were referred to our multisite consortium. We measured nasal nitric oxide (nNO) level, examined cilia with electron microscopy, and analyzed PCD-causing gene mutations. Situs was classified as (1) situs solitus (SS), (2) SI, or (3) situs ambiguus (SA), including heterotaxy. Participants with hallmark electron microscopic defects, biallelic gene mutations, or both were considered to have classic PCD.

RESULTS: Of 767 participants (median age, 8.1 years, range, 0.1-58 years), classic PCD was defined in 305, including 143 (46.9\%), 125 (41.0\%), and 37 (12.1\%) with SS, SI, and SA, respectively. A spectrum of laterality defects was identified with classic PCD, including 2.6\% and 2.3\% with SA plus complex or simple cardiac defects, respectively; 4.6\% with SA but no cardiac defect; and 2.6\% with an isolated possible laterality defect. Participants with SA and classic PCD had a higher prevalence of PCD-associated respiratory symptoms vs SA control participants (year-round wet cough, P < .001; year-round nasal congestion, P = .015; neonatal respiratory distress, P = .009; digital clubbing, P = .021) and lower nNO levels (median, 12 nL/min vs 252 nL/min; P < .001).

CONCLUSIONS: At least 12.1\% of patients with classic PCD have SA and laterality defects ranging from classic heterotaxy to subtle laterality defects. Specific clinical features of PCD and low nNO levels help to identify PCD in patients with laterality defects.

TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00323167; URL: www.clinicaltrials.gov.

}, keywords = {Adolescent, Adult, Biopsy, Child, Child, Preschool, Cilia, DNA, DNA Mutational Analysis, Female, Humans, Infant, Infant, Newborn, Kartagener Syndrome, Male, Microscopy, Electron, Transmission, Middle Aged, Mutation, Prevalence, Prospective Studies, Tomography, X-Ray Computed, United States, Young Adult}, issn = {1931-3543}, doi = {10.1378/chest.13-1704}, author = {Shapiro, Adam J and Davis, Stephanie D and Ferkol, Thomas and Dell, Sharon D and Rosenfeld, Margaret and Olivier, Kenneth N and Sagel, Scott D and Milla, Carlos and Zariwala, Maimoona A and Wolf, Whitney and Carson, Johnny L and Hazucha, Milan J and Burns, Kimberlie and Robinson, Blair and Knowles, Michael R and Leigh, Margaret W} } @article {273, title = {Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Jun 01}, pages = {2888-900}, abstract = {

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80\% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for \~{}5\% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

}, keywords = {Amino Acid Sequence, Child, Child, Preschool, Cohort Studies, Cranial Fontanelles, De Lange Syndrome, Eye Abnormalities, Female, Genes, X-Linked, Histone Deacetylases, Humans, Hypertelorism, Infant, Male, Molecular Sequence Data, Mutation, Missense, Phenotype, Repressor Proteins, Sequence Alignment}, issn = {1460-2083}, doi = {10.1093/hmg/ddu002}, author = {Kaiser, Frank J and Ansari, Morad and Braunholz, Diana and Concepci{\'o}n Gil-Rodr{\'\i}guez, Mar{\'\i}a and Decroos, Christophe and Wilde, Jonathan J and Fincher, Christopher T and Kaur, Maninder and Bando, Masashige and Amor, David J and Atwal, Paldeep S and Bahlo, Melanie and Bowman, Christine M and Bradley, Jacquelyn J and Brunner, Han G and Clark, Dinah and Del Campo, Miguel and Di Donato, Nataliya and Diakumis, Peter and Dubbs, Holly and Dyment, David A and Eckhold, Juliane and Ernst, Sarah and Ferreira, Jose C and Francey, Lauren J and Gehlken, Ulrike and Guill{\'e}n-Navarro, Encarna and Gyftodimou, Yolanda and Hall, Bryan D and Hennekam, Raoul and Hudgins, Louanne and Hullings, Melanie and Hunter, Jennifer M and Yntema, Helger and Innes, A Micheil and Kline, Antonie D and Krumina, Zita and Lee, Hane and Leppig, Kathleen and Lynch, Sally Ann and Mallozzi, Mark B and Mannini, Linda and McKee, Shane and Mehta, Sarju G and Micule, Ieva and Mohammed, Shehla and Moran, Ellen and Mortier, Geert R and Moser, Joe-Ann S and Noon, Sarah E and Nozaki, Naohito and Nunes, Luis and Pappas, John G and Penney, Lynette S and P{\'e}rez-Ayt{\'e}s, Antonio and Petersen, Michael B and Puisac, Beatriz and Revencu, Nicole and Roeder, Elizabeth and Saitta, Sulagna and Scheuerle, Angela E and Schindeler, Karen L and Siu, Victoria M and Stark, Zornitza and Strom, Samuel P and Thiese, Heidi and Vater, Inga and Willems, Patrick and Williamson, Kathleen and Wilson, Louise C and Hakonarson, Hakon and Quintero-Rivera, Fabiola and Wierzba, Jolanta and Musio, Antonio and Gillessen-Kaesbach, Gabriele and Ramos, Feliciano J and Jackson, Laird G and Shirahige, Katsuhiko and Pi{\'e}, Juan and Christianson, David W and Krantz, Ian D and FitzPatrick, David R and Deardorff, Matthew A} } @article {217, title = {Molecular findings among patients referred for clinical whole-exome sequencing.}, journal = {JAMA}, volume = {312}, year = {2014}, month = {2014 Nov 12}, pages = {1870-9}, abstract = {

IMPORTANCE: Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.

OBJECTIVE: To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.

DESIGN, SETTING, AND PATIENTS: Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient{\textquoteright}s physician. The patients were primarily pediatric (1756 [88\%]; mean age, 6 years; 888 females [44\%], 1101 males [55\%], and 11 fetuses [1\% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.

MAIN OUTCOMES AND MEASURES: Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.

RESULTS: A molecular diagnosis was reported for 504 patients (25.2\%) with 58\% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2\%; 95\% CI, 23.5\%-31.2\%) for the neurological group, 282/1147 (24.6\%; 95\% CI, 22.1\%-27.2\%) for the neurological plus other organ systems group, 30/83 (36.1\%; 95\% CI, 26.1\%-47.5\%) for the specific neurological group, and 49/244 (20.1\%; 95\% CI, 15.6\%-25.8\%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1\%) autosomal dominant, 181 (34.3\%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3\%) X-linked, and 1 (0.2\%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6\%) had blended phenotypes resulting from 2 single gene defects. About 30\% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6\%), including 59 patients (3\%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.

CONCLUSIONS AND RELEVANCE: Whole-exome sequencing provided a potential molecular diagnosis for 25\% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Exome, Female, Fetus, Genetic Diseases, Inborn, Genetic Testing, Genomics, Humans, Incidental Findings, Infant, Infant, Newborn, Male, Molecular Diagnostic Techniques, Mutation, Phenotype, Referral and Consultation, Sequence Analysis, DNA}, issn = {1538-3598}, doi = {10.1001/jama.2014.14601}, author = {Yang, Yaping and Muzny, Donna M and Xia, Fan and Niu, Zhiyv and Person, Richard and Ding, Yan and Ward, Patricia and Braxton, Alicia and Wang, Min and Buhay, Christian and Veeraraghavan, Narayanan and Hawes, Alicia and Chiang, Theodore and Leduc, Magalie and Beuten, Joke and Zhang, Jing and He, Weimin and Scull, Jennifer and Willis, Alecia and Landsverk, Megan and Craigen, William J and Bekheirnia, Mir Reza and Stray-Pedersen, Asbjorg and Liu, Pengfei and Wen, Shu and Alcaraz, Wendy and Cui, Hong and Walkiewicz, Magdalena and Reid, Jeffrey and Bainbridge, Matthew and Patel, Ankita and Boerwinkle, Eric and Beaudet, Arthur L and Lupski, James R and Plon, Sharon E and Gibbs, Richard A and Eng, Christine M} } @article {275, title = {Mutations in PCYT1A, encoding a key regulator of phosphatidylcholine metabolism, cause spondylometaphyseal dysplasia with cone-rod dystrophy.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jan 02}, pages = {105-12}, keywords = {Alleles, Child, Preschool, Choline-Phosphate Cytidylyltransferase, Female, Humans, Infant, Male, Middle Aged, Mutation, Missense, Osteochondrodysplasias, Pedigree, Phosphatidylcholines, Retinitis Pigmentosa}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.11.018}, author = {Hoover-Fong, Julie and Sobreira, Nara and Jurgens, Julie and Modaff, Peggy and Blout, Carrie and Moser, Ann and Kim, Ok-Hwa and Cho, Tae-Joon and Cho, Sung Yoon and Kim, Sang Jin and Jin, Dong-Kyu and Kitoh, Hiroshi and Park, Woong-Yang and Ling, Hua and Hetrick, Kurt N and Doheny, Kimberly F and Valle, David and Pauli, Richard M} } @article {292, title = {Neonatal diabetes, gallbladder agenesis, duodenal atresia, and intestinal malrotation caused by a novel homozygous mutation in RFX6.}, journal = {Pediatr Diabetes}, volume = {15}, year = {2014}, month = {2014 Feb}, pages = {67-72}, abstract = {

Recently, bi-allelic mutations in the transcription factor RFX6 were described as the cause of a rare condition characterized by neonatal diabetes with pancreatic and biliary hypoplasia and duodenal/jejunal atresia. A male infant developed severe hyperglycemia (446 mg/dL) within 24 h of birth. Acute abdominal concerns by day five necessitated exploratory surgery that revealed duodenal atresia, gallbladder agenesis, annular pancreas and intestinal malrotation. He also exhibited chronic diarrhea and feeding intolerance, cholestatic jaundice, and subsequent liver failure. He died of sepsis at four months old while awaiting liver transplantation. The phenotype of neonatal diabetes with intestinal atresia and biliary agenesis clearly pointed to RFX6 as the causative gene; indeed, whole exome sequencing revealed a novel homozygous RFX6 mutation c.779A>C; p.Lys260Thr (K260T). This missense mutation also changes the consensus 5{\textquoteright} splice donor site before intron 7 and is thus predicted to cause disruption in splicing. Both parents, who were not known to be related, were heterozygous carriers. Targeted genetic testing based on consideration of phenotypic features may reveal a cause among the many genes now associated with heterogeneous forms of monogenic neonatal diabetes. Our study demonstrates the feasibility of using modern sequencing technology to identify one such rare cause. Continued research is needed to determine the possible cost-effectiveness of this approach, especially when clear phenotypic clues are absent. Further study of patients with RFX6 mutations should clarify its role in pancreatic, intestinal and enteroendocrine cellular development and explain features such as the diarrhea exhibited in our case.

}, keywords = {Abnormalities, Multiple, Congenital Abnormalities, Diabetes Mellitus, Type 1, Digestive System Abnormalities, DNA-Binding Proteins, Duodenal Obstruction, Fatal Outcome, Gallbladder, Humans, Infant, Infant, Newborn, Infant, Newborn, Diseases, Intestinal Atresia, Intestinal Volvulus, Male, Pancreas, Pancreatic Diseases, Regulatory Factor X Transcription Factors, Transcription Factors}, issn = {1399-5448}, doi = {10.1111/pedi.12063}, author = {Concepcion, Jennifer P and Reh, Christina S and Daniels, Mark and Liu, Xiaoming and Paz, Veronica P and Ye, Honggang and Highland, Heather M and Hanis, Craig L and Greeley, Siri Atma W} } @article {239, title = {Opsismodysplasia resulting from an insertion mutation in the SH2 domain, which destabilizes INPPL1.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 Sep}, pages = {2407-11}, keywords = {Adolescent, Amino Acid Sequence, Base Sequence, Child, Child, Preschool, Female, Humans, Infant, Molecular Sequence Data, Mutagenesis, Insertional, Mutation, Osteochondrodysplasias, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases, Protein Stability, Radiography, RNA Splice Sites, src Homology Domains}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36640}, author = {Li, Bing and Krakow, Deborah and Nickerson, Deborah A and Bamshad, Michael J and Chang, Yong and Lachman, Ralph S and Yilmaz, Alev and Kayserili, H{\"u}lya and Cohn, Daniel H} } @article {232, title = {Vaccine-associated varicella and rubella infections in severe combined immunodeficiency with isolated CD4 lymphocytopenia and mutations in IL7R detected by tandem whole exome sequencing and chromosomal microarray.}, journal = {Clin Exp Immunol}, volume = {178}, year = {2014}, month = {2014 Dec}, pages = {459-69}, abstract = {

In areas without newborn screening for severe combined immunodeficiency (SCID), disease-defining infections may lead to diagnosis, and in some cases, may not be identified prior to the first year of life. We describe a female infant who presented with disseminated vaccine-acquired varicella (VZV) and vaccine-acquired rubella infections at 13 months of age. Immunological evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, the presence of CD8(+) T cells, poor lymphocyte proliferation, hypergammaglobulinaemia and poor specific antibody production to VZV infection and routine immunizations. A combination of whole exome sequencing and custom-designed chromosomal microarray with exon coverage of primary immunodeficiency genes detected compound heterozygous mutations (one single nucleotide variant and one intragenic copy number variant involving one exon) within the IL7R gene. Mosaicism for wild-type allele (20-30\%) was detected in pretransplant blood and buccal DNA and maternal engraftment (5-10\%) demonstrated in pretransplant blood DNA. This may be responsible for the patient{\textquoteright}s unusual immunological phenotype compared to classical interleukin (IL)-7Rα deficiency. Disseminated VZV was controlled with anti-viral and immune-based therapy, and umbilical cord blood stem cell transplantation was successful. Retrospectively performed T cell receptor excision circle (TREC) analyses completed on neonatal Guthrie cards identified absent TREC. This case emphasizes the danger of live viral vaccination in severe combined immunodeficiency (SCID) patients and the importance of newborn screening to identify patients prior to high-risk exposures. It also illustrates the value of aggressive pathogen identification and treatment, the influence newborn screening can have on morbidity and mortality and the significant impact of newer genomic diagnostic tools in identifying the underlying genetic aetiology for SCID patients.

}, keywords = {CD4-Positive T-Lymphocytes, Chickenpox, DNA Copy Number Variations, Exome, Female, Humans, Infant, Lymphopenia, Mutation, Oligonucleotide Array Sequence Analysis, Receptors, Interleukin-7, Rubella, Severe Combined Immunodeficiency, Vaccination}, issn = {1365-2249}, doi = {10.1111/cei.12421}, author = {Bayer, D K and Martinez, C A and Sorte, H S and Forbes, L R and Demmler-Harrison, G J and Hanson, I C and Pearson, N M and Noroski, L M and Zaki, S R and Bellini, W J and Leduc, M S and Yang, Y and Eng, C M and Patel, A and Rodningen, O K and Muzny, D M and Gibbs, R A and Campbell, I M and Shaw, C A and Baker, M W and Zhang, V and Lupski, J R and Orange, J S and Seeborg, F O and Stray-Pedersen, A} } @article {272, title = {Whole-exome sequencing links TMCO1 defect syndrome with cerebro-facio-thoracic dysplasia.}, journal = {Eur J Hum Genet}, volume = {22}, year = {2014}, month = {2014 Sep}, pages = {1145-8}, abstract = {

Whole-exome sequencing (WES) is a type of disruptive technology that has tremendous influence on human and clinical genetics research. An efficient and cost-effective method, WES is now widely used as a diagnostic tool for identifying the molecular basis of genetic syndromes that are often challenging to diagnose. Here we report a patient with a clinical diagnosis of cerebro-facio-thoracic dysplasia (CFTD; MIM$\#$213980) in whom we identified a homozygous splice-site mutation in the transmembrane and coiled-coil domains 1 (TMCO1) gene using WES. TMCO1 mutations cause craniofacial dysmorphism, skeletal anomalies characterized by multiple malformations of the vertebrae and ribs, and intellectual disability (MIM$\#$614132). A retrospective review revealed that clinical manifestations of both syndromes are very similar and overlap remarkably. We propose that mutations of TMCO1 are not only responsible for craniofacial dysmorphism, skeletal anomalies and mental retardation syndrome but also for CFTD.

}, keywords = {Abnormalities, Multiple, Exome, Humans, Infant, Intellectual Disability, Male, Membrane Proteins, Mutation, Protein Isoforms}, issn = {1476-5438}, doi = {10.1038/ejhg.2013.291}, author = {Pehlivan, Davut and Karaca, Ender and Aydin, Hatip and Beck, Christine R and Gambin, Tomasz and Muzny, Donna M and Bilge Geckinli, B and Karaman, Ali and Jhangiani, Shalini N and Gibbs, Richard A and Lupski, James R} } @article {259, title = {Whole-exome sequencing reveals GPIHBP1 mutations in infantile colitis with severe hypertriglyceridemia.}, journal = {J Pediatr Gastroenterol Nutr}, volume = {59}, year = {2014}, month = {2014 Jul}, pages = {17-21}, abstract = {

Severe congenital hypertriglyceridemia (HTG) is a rare disorder caused by mutations in genes affecting lipoprotein lipase (LPL) activity. Here we report a 5-week-old Hispanic girl with severe HTG (12,031 mg/dL, normal limit 150 mg/dL) who presented with the unusual combination of lower gastrointestinal bleeding and milky plasma. Initial colonoscopy was consistent with colitis, which resolved with reduction of triglycerides. After negative sequencing of the LPL gene, whole-exome sequencing revealed novel compound heterozygous mutations in GPIHBP1. Our study broadens the phenotype of GPIHBP1-associated HTG, reinforces the effectiveness of whole-exome sequencing in Mendelian diagnoses, and implicates triglycerides in gastrointestinal mucosal injury.

}, keywords = {Colitis, DNA Mutational Analysis, Exome, Female, Humans, Hypertriglyceridemia, Infant, Receptors, Lipoprotein}, issn = {1536-4801}, doi = {10.1097/MPG.0000000000000363}, author = {Gonzaga-Jauregui, Claudia and Mir, Sabina and Penney, Samantha and Jhangiani, Shalini and Midgen, Craig and Finegold, Milton and Muzny, Donna M and Wang, Min and Bacino, Carlos A and Gibbs, Richard A and Lupski, James R and Kellermayer, Richard and Hanchard, Neil A} } @article {295, title = {Mutations in DSTYK and dominant urinary tract malformations.}, journal = {N Engl J Med}, volume = {369}, year = {2013}, month = {2013 Aug 15}, pages = {621-9}, abstract = {

BACKGROUND: Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.

METHODS: We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies.

RESULTS: Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.

CONCLUSIONS: We detected independent DSTYK mutations in 2.3\% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

}, keywords = {Adult, Animals, Base Sequence, Child, Exome, Female, Gene Knockdown Techniques, Genetic Linkage, Genome-Wide Association Study, Heterozygote, Humans, Infant, Kidney, Male, Mice, Molecular Sequence Data, Mutation, Pedigree, Receptor-Interacting Protein Serine-Threonine Kinases, RNA, Small Interfering, Urinary Tract, Urogenital Abnormalities, Young Adult}, issn = {1533-4406}, doi = {10.1056/NEJMoa1214479}, author = {Sanna-Cherchi, Simone and Sampogna, Rosemary V and Papeta, Natalia and Burgess, Katelyn E and Nees, Shannon N and Perry, Brittany J and Choi, Murim and Bodria, Monica and Liu, Yan and Weng, Patricia L and Lozanovski, Vladimir J and Verbitsky, Miguel and Lugani, Francesca and Sterken, Roel and Paragas, Neal and Caridi, Gianluca and Carrea, Alba and Dagnino, Monica and Materna-Kiryluk, Anna and Santamaria, Giuseppe and Murtas, Corrado and Ristoska-Bojkovska, Nadica and Izzi, Claudia and Kacak, Nilgun and Bianco, Beatrice and Giberti, Stefania and Gigante, Maddalena and Piaggio, Giorgio and Gesualdo, Loreto and Vukic, Durdica Kosuljandic and Vukojevic, Katarina and Saraga-Babic, Mirna and Saraga, Marijan and Gucev, Zoran and Allegri, Landino and Latos-Bielenska, Anna and Casu, Domenica and State, Matthew and Scolari, Francesco and Ravazzolo, Roberto and Kiryluk, Krzysztof and Al-Awqati, Qais and D{\textquoteright}Agati, Vivette D and Drummond, Iain A and Tasic, Velibor and Lifton, Richard P and Ghiggeri, Gian Marco and Gharavi, Ali G} } @article {287, title = {Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly.}, journal = {JAMA Neurol}, volume = {70}, year = {2013}, month = {2013 Dec}, pages = {1491-8}, abstract = {

IMPORTANCE: Patients with rare diseases and complex clinical presentations represent a challenge for clinical diagnostics. Genomic approaches are allowing the identification of novel variants in genes for very rare disorders, enabling a molecular diagnosis. Genomics is also revealing a phenotypic expansion whereby the full spectrum of clinical expression conveyed by mutant alleles at a locus can be better appreciated.

OBJECTIVE: To elucidate the molecular cause of a complex neuropathy phenotype in 3 patients by applying genomic sequencing strategies.

DESIGN, SETTING, AND PARTICIPANTS: Three affected individuals from 2 unrelated families presented with a complex neuropathy phenotype characterized by axonal sensorimotor neuropathy and microcephaly. They were recruited into the Centers for Mendelian Genomics research program to identify the molecular cause of their phenotype. Whole-genome, targeted whole-exome sequencing, and high-resolution single-nucleotide polymorphism arrays were performed in genetics clinics of tertiary care pediatric hospitals and biomedical research institutions.

MAIN OUTCOMES AND MEASURES: Whole-genome and whole-exome sequencing identified the variants responsible for the patients{\textquoteright} clinical phenotype.

RESULTS: We identified compound heterozygous alleles in 2 affected siblings from 1 family and a homozygous nonsense variant in the third unrelated patient in the vaccinia-related kinase 1 gene (VRK1). In the latter subject, we found a common haplotype on which the nonsense mutation occurred and that segregates in the Ashkenazi Jewish population.

CONCLUSIONS AND RELEVANCE: We report the identification of disease-causing alleles in 3 children from 2 unrelated families with a previously uncharacterized complex axonal motor and sensory neuropathy accompanied by severe nonprogressive microcephaly and cerebral dysgenesis. Our data raise the question of whether VRK1 mutations disturb cell cycle progression and may result in apoptosis of cells in the nervous system. The application of unbiased genomic approaches allows the identification of potentially pathogenic mutations in unsuspected genes in highly genetically heterogeneous and uncharacterized neurological diseases.

}, keywords = {Child, Child, Preschool, DNA Mutational Analysis, Female, Genotype, Hereditary Sensory and Motor Neuropathy, Humans, Infant, Intracellular Signaling Peptides and Proteins, Magnetic Resonance Imaging, Male, Microcephaly, Mutation, Neural Conduction, Polymorphism, Single Nucleotide, Protein-Serine-Threonine Kinases}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2013.4598}, author = {Gonzaga-Jauregui, Claudia and Lotze, Timothy and Jamal, Leila and Penney, Samantha and Campbell, Ian M and Pehlivan, Davut and Hunter, Jill V and Woodbury, Suzanne L and Raymond, Gerald and Adesina, Adekunle M and Jhangiani, Shalini N and Reid, Jeffrey G and Muzny, Donna M and Boerwinkle, Eric and Lupski, James R and Gibbs, Richard A and Wiszniewski, Wojciech} } @article {306, title = {Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 May}, pages = {531-6}, abstract = {

Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase ɛ) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid-containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS.

}, keywords = {Acute Kidney Injury, Atypical Hemolytic Uremic Syndrome, Child, Child, Preschool, Diacylglycerol Kinase, Exome, Female, Genes, Recessive, Hemolytic-Uremic Syndrome, Humans, Immunoenzyme Techniques, Infant, Male, Molecular Sequence Data, Mutation, Renal Insufficiency, Chronic, Thrombocytopenia, Thrombotic Microangiopathies}, issn = {1546-1718}, doi = {10.1038/ng.2590}, author = {Lemaire, Mathieu and Fremeaux-Bacchi, Veronique and Schaefer, Franz and Choi, Murim and Tang, Wai Ho and Le Quintrec, Moglie and Fakhouri, Fadi and Taque, Sophie and Nobili, Fran{\c c}ois and Martinez, Frank and Ji, Weizhen and Overton, John D and Mane, Shrikant M and N{\"u}rnberg, Gudrun and Altm{\"u}ller, Janine and Thiele, Holger and Morin, Denis and Deschenes, Georges and Baudouin, V{\'e}ronique and Llanas, Brigitte and Collard, Laure and Majid, Mohammed A and Simkova, Eva and N{\"u}rnberg, Peter and Rioux-Leclerc, Nathalie and Moeckel, Gilbert W and Gubler, Marie Claire and Hwa, John and Loirat, Chantal and Lifton, Richard P} } @article {318, title = {Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus.}, journal = {J Invest Dermatol}, volume = {133}, year = {2013}, month = {2013 Mar}, pages = {827-830}, keywords = {Adolescent, Adult, Amino Acid Sequence, Biopsy, Child, Child, Preschool, Cohort Studies, Epidermis, Exome, Humans, Infant, Middle Aged, Molecular Sequence Data, Mutation, Nevus, Sebaceous of Jadassohn, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), ras Proteins, Sequence Analysis, DNA, Young Adult}, issn = {1523-1747}, doi = {10.1038/jid.2012.379}, author = {Levinsohn, Jonathan L and Tian, Li C and Boyden, Lynn M and McNiff, Jennifer M and Narayan, Deepak and Loring, Erin S and Yun, Duri and Sugarman, Jeffrey L and Overton, John D and Mane, Shrikant M and Lifton, Richard P and Paller, Amy S and Wagner, Annette M and Antaya, Richard J and Choate, Keith A} } @article {313, title = {Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Jan 10}, pages = {137-43}, abstract = {

Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ~60\% of cases overall, including both of the families in our cohort with more than one affected child and 50\% of the simplex cases.

}, keywords = {Child, Child, Preschool, Female, Genome, Human, Humans, Infant, Infant, Newborn, Male, Mutation, Osteochondrodysplasias, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2012.11.011}, author = {Below, Jennifer E and Earl, Dawn L and Shively, Kathryn M and McMillin, Margaret J and Smith, Joshua D and Turner, Emily H and Stephan, Mark J and Al-Gazali, Lihadh I and Hertecant, Jozef L and Chitayat, David and Unger, Sheila and Cohn, Daniel H and Krakow, Deborah and Swanson, James M and Faustman, Elaine M and Shendure, Jay and Nickerson, Deborah A and Bamshad, Michael J} }