@article {983, title = {Perturbations of genes essential for M{\"u}llerian duct and W{\"o}lffian duct development in Mayer-Rokitansky-K{\"u}ster-Hauser syndrome.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 02 04}, pages = {337-345}, abstract = {

Mayer-Rokitansky-K{\"u}ster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the M{\"u}llerian ducts (MD)/W{\"o}lffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.

}, keywords = {46, XX Disorders of Sex Development, Adult, Bone Morphogenetic Protein 4, Bone Morphogenetic Protein 7, Codon, Nonsense, Congenital Abnormalities, Female, Genetic Association Studies, Genetic Pleiotropy, Homeobox A10 Proteins, Homeodomain Proteins, Humans, Mullerian Ducts, Mutation, Paternal Inheritance, PAX8 Transcription Factor, Penetrance, T-Box Domain Proteins, Transcription Factors, Wnt Proteins, Wolffian Ducts}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.12.014}, author = {Chen, Na and Zhao, Sen and Jolly, Angad and Wang, Lianlei and Pan, Hongxin and Yuan, Jian and Chen, Shaoke and Koch, Andr{\'e} and Ma, Congcong and Tian, Weijie and Jia, Ziqi and Kang, Jia and Zhao, Lina and Qin, Chenglu and Fan, Xin and Rall, Katharina and Coban-Akdemir, Zeynep and Chen, Zefu and Jhangiani, Shalini and Liang, Ze and Niu, Yuchen and Li, Xiaoxin and Yan, Zihui and Wu, Yong and Dong, Shuangshuang and Song, Chengcheng and Qiu, Guixing and Zhang, Shuyang and Liu, Pengfei and Posey, Jennifer E and Zhang, Feng and Luo, Guangnan and Wu, Zhihong and Su, Jianzhong and Zhang, Jianguo and Chen, Eugenia Y and Rouskas, Konstantinos and Glentis, Stavros and Bacopoulou, Flora and Deligeoroglou, Efthymios and Chrousos, George and Lyonnet, Stanislas and Polak, Michel and Rosenberg, Carla and Dingeldein, Irene and Bonilla, Ximena and Borel, Christelle and Gibbs, Richard A and Dietrich, Jennifer E and Dimas, Antigone S and Antonarakis, Stylianos E and Brucker, Sara Y and Lupski, James R and Wu, Nan and Zhu, Lan} } @article {766, title = {Expanding the phenotypic spectrum in RDH12-associated retinal disease.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {6}, year = {2020}, month = {2020 02}, abstract = {

Retinol dehydrogenase 12, RDH12, plays a pivotal role in the visual cycle to ensure the maintenance of normal vision. Alterations in activity of this protein result in photoreceptor death and decreased vision beginning at an early age and progressing to substantial vision loss later in life. Here we describe 11 patients with retinal degeneration that underwent next-generation sequencing (NGS) with a targeted panel of all currently known inherited retinal degeneration (IRD) genes and whole-exome sequencing to identify the genetic causality of their retinal disease. These patients display a range of phenotypic severity prompting clinical diagnoses of macular dystrophy, cone-rod dystrophy, retinitis pigmentosa, and early-onset severe retinal dystrophy all attributed to biallelic recessive mutations in We report 15 causal alleles and expand the repertoire of known mutations with four novel variants: c.215A > G (p.Asp72Gly); c.362T > C (p.Ile121Thr); c.440A > C (p.Asn147Thr); and c.697G > A (p.Val233Ille). The broad phenotypic spectrum observed with biallelic mutations has been observed in other genetic forms of IRDs, but the diversity is particularly notable here given the prior association of primarily with severe early-onset disease. This breadth emphasizes the importance of broad genetic testing for inherited retinal disorders and extends the pool of individuals who may benefit from imminent gene-targeted therapies.

}, keywords = {Adolescent, Adult, Alcohol Oxidoreductases, Alleles, Amino Acid Substitution, Child, Child, Preschool, Female, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Humans, Male, Mutation, Optical Imaging, Pedigree, Phenotype, Retinal Diseases, Tomography, Optical Coherence, Whole Exome Sequencing, Young Adult}, issn = {2373-2873}, doi = {10.1101/mcs.a004754}, author = {Scott, Hilary A and Place, Emily M and Ferenchak, Kevin and Zampaglione, Erin and Wagner, Naomi E and Chao, Katherine R and DiTroia, Stephanie P and Navarro-Gomez, Daniel and Mukai, Shizuo and Huckfeldt, Rachel M and Pierce, Eric A and Bujakowska, Kinga M} } @article {917, title = {Human CRY1 variants associate with attention deficit/hyperactivity disorder.}, journal = {J Clin Invest}, volume = {130}, year = {2020}, month = {2020 07 01}, pages = {3885-3900}, abstract = {

Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1\% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders.

}, keywords = {Adult, ARNTL Transcription Factors, Attention Deficit Disorder with Hyperactivity, CLOCK Proteins, Cryptochromes, Female, Genetic Association Studies, HEK293 Cells, Humans, Male, Mutation, Sleep Disorders, Circadian Rhythm}, issn = {1558-8238}, doi = {10.1172/JCI135500}, author = {Onat, O Emre and Kars, M Ece and G{\"u}l, {\c S}eref and Bilguvar, Kaya and Wu, Yiming and {\"O}zhan, Ay{\c s}e and Ayd{\i}n, Cihan and Ba{\c s}ak, A Nazl{\i} and Trusso, M Allegra and Goracci, Arianna and Fallerini, Chiara and Renieri, Alessandra and Casanova, Jean-Laurent and Itan, Yuval and Atba{\c s}o{\u g}lu, Cem E and Saka, Meram C and Kavakl{\i}, {\.I} Halil and Ozcelik, Tayfun} } @article {978, title = {POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern.}, journal = {Acta Neuropathol}, volume = {139}, year = {2020}, month = {2020 03}, pages = {565-582}, abstract = {

Protein O-glucosyltransferase 1 (POGLUT1) activity is critical for the Notch signaling pathway, being one of the main enzymes responsible for the glycosylation of the extracellular domain of Notch receptors. A biallelic mutation in the POGLUT1 gene has been reported in one family as the cause of an adult-onset limb-girdle muscular dystrophy (LGMD R21; OMIM$\#$ 617232). As the result of a collaborative international effort, we have identified the first cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries, providing a reliable phenotype-genotype and mechanistic insight. Patients carrying novel mutations in POGLUT1 all displayed a clinical picture of limb-girdle muscle weakness. However, the age at onset was broadened from adult to congenital and infantile onset. Moreover, we now report that the unique muscle imaging pattern of "inside-to-outside" fatty degeneration observed in the original cases is indeed a defining feature of POGLUT1 muscular dystrophy. Experiments on muscle biopsies from patients revealed a remarkable and consistent decrease in the level of the NOTCH1 intracellular domain, reduction of the pool of satellite cells (SC), and evidence of α-dystroglycan hypoglycosylation. In vitro biochemical and cell-based assays suggested a pathogenic role of the novel POGLUT1 mutations, leading to reduced enzymatic activity and/or protein stability. The association between the POGLUT1 variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenic Drosophila, showing that the human POGLUT1 mutations reduced its myogenic activity. In line with the well-known role of the Notch pathway in the homeostasis of SC and muscle regeneration, SC-derived myoblasts from patients{\textquoteright} muscle samples showed decreased proliferation and facilitated differentiation. Together, these observations suggest that alterations in SC biology caused by reduced Notch1 signaling result in muscular dystrophy in LGMD R21 patients, likely with additional contribution from α-dystroglycan hypoglycosylation. This study settles the muscular clinical phenotype linked to POGLUT1 mutations and establishes the pathogenic mechanism underlying this muscle disorder. The description of a specific imaging pattern of fatty degeneration and muscle pathology with a decrease of α-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients.

}, keywords = {Animals, Animals, Genetically Modified, Drosophila melanogaster, Dystroglycans, Female, Genetic Association Studies, Glucosyltransferases, Glycosylation, Humans, Male, Muscle, Skeletal, Muscular Dystrophies, Limb-Girdle, Mutation, Pedigree, Satellite Cells, Skeletal Muscle}, issn = {1432-0533}, doi = {10.1007/s00401-019-02117-6}, author = {Servi{\'a}n-Morilla, E and Cabrera-Serrano, M and Johnson, K and Pandey, A and Ito, A and Rivas, E and Chamova, T and Muelas, N and Mongini, T and Nafissi, S and Claeys, K G and Grewal, R P and Takeuchi, M and Hao, H and B{\"o}nnemann, C and Lopes Abath Neto, O and Medne, L and Brandsema, J and T{\"o}pf, A and Taneva, A and Vilchez, J J and Tournev, I and Haltiwanger, R S and Takeuchi, H and Jafar-Nejad, H and Straub, V and Paradas, Carmen} } @article {816, title = {Spectrum of genetic variants in moderate to severe sporadic hearing loss in Pakistan.}, journal = {Sci Rep}, volume = {10}, year = {2020}, month = {2020 07 17}, pages = {11902}, abstract = {

Hearing loss affects 380 million people worldwide due to environmental or genetic causes. Determining the cause of deafness in individuals without previous family history of hearing loss is challenging and has been relatively unexplored in Pakistan. We investigated the spectrum of genetic variants in hearing loss in a cohort of singleton affected individuals born to consanguineous parents. Twenty-one individuals with moderate to severe hearing loss were recruited. We performed whole-exome sequencing on DNA samples from the participants, which identified seventeen variants in ten known deafness genes and one novel candidate gene. All identified variants were homozygous except for two. Eleven of the variants were novel, including one multi-exonic homozygous deletion in OTOA. A missense variant in ESRRB was implicated for recessively inherited moderate to severe hearing loss. Two individuals were heterozygous for variants in MYO7A and CHD7, respectively, consistent with de novo variants or dominant inheritance with incomplete penetrance as the reason for their hearing loss. Our results indicate that similar to familial cases of deafness, variants in a large number of genes are responsible for moderate to severe hearing loss in sporadic individuals born to consanguineous couples.

}, keywords = {Adolescent, Amino Acid Sequence, Audiometry, Pure-Tone, Child, Child, Preschool, Deafness, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Hearing Loss, Heterozygote, Homozygote, Humans, Mutation, Missense, Pakistan, Phenotype, Whole Exome Sequencing, Young Adult}, issn = {2045-2322}, doi = {10.1038/s41598-020-68779-5}, author = {Ramzan, Memoona and Bashir, Rasheeda and Salman, Midhat and Mujtaba, Ghulam and Sobreira, Nara and Witmer, P Dane and Naz, Sadaf} } @article {774, title = {TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 01}, pages = {182-195}, abstract = {

Congenital scoliosis (CS) is a birth defect with variable clinical and anatomical manifestations due to spinal malformation. The genetic etiology underlying about 10\% of CS cases in the Chinese population is compound inheritance by which the gene dosage is reduced below that of haploinsufficiency. In this genetic model, the trait manifests as a result of the combined effect of a rare variant and common pathogenic variant allele at a locus. From exome sequencing (ES) data of 523 patients in Asia and two patients in Texas, we identified six TBX6 gene-disruptive variants from 11 unrelated CS patients via ES and in vitro functional testing. The in trans mild hypomorphic allele was identified in 10 of the 11 subjects; as anticipated these 10 shared a similar spinal deformity of hemivertebrae. The remaining case has a homozygous variant in TBX6 (c.418C>T) and presents a more severe spinal deformity phenotype. We found decreased transcriptional activity and abnormal cellular localization as the molecular mechanisms for TBX6 missense loss-of-function alleles. Expanding the mutational spectrum of TBX6 pathogenic alleles enabled an increased molecular diagnostic detection rate, provided further evidence for the gene dosage-dependent genetic model underlying CS, and refined clinical classification.

}, keywords = {Alleles, Cell Line, Female, Gene Expression, Genes, Reporter, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Inheritance Patterns, Male, Models, Molecular, Molecular Diagnostic Techniques, Mutation, Missense, Phenotype, Protein Conformation, Radiography, Sequence Analysis, DNA, Spine, Structure-Activity Relationship, T-Box Domain Proteins, Whole Exome Sequencing}, issn = {1098-1004}, doi = {10.1002/humu.23907}, author = {Chen, Weisheng and Lin, Jiachen and Wang, Lianlei and Li, Xiaoxin and Zhao, Sen and Liu, Jiaqi and Akdemir, Zeynep C and Zhao, Yanxue and Du, Renqian and Ye, Yongyu and Song, Xiaofei and Zhang, Yuanqiang and Yan, Zihui and Yang, Xinzhuang and Lin, Mao and Shen, Jianxiong and Wang, Shengru and Gao, Na and Yang, Ying and Liu, Ying and Li, Wenli and Liu, Jia and Zhang, Na and Yang, Xu and Xu, Yuan and Zhang, Jianguo and Delgado, Mauricio R and Posey, Jennifer E and Qiu, Guixing and Rios, Jonathan J and Liu, Pengfei and Wise, Carol A and Zhang, Feng and Wu, Zhihong and Lupski, James R and Wu, Nan} } @article {761, title = {Wolff-Parkinson-White syndrome: De novo variants and evidence for mutational burden in genes associated with atrial fibrillation.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 06}, pages = {1387-1399}, abstract = {

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population.

METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, candidate gene approach, and burden testing to explore the genetic contributions to WPW.

RESULTS: A heterozygous deleterious variant in PRKAG2 was identified in one subject, accounting for 0.6\% (1/151) of the genetic basis of WPW in this study. Another individual with WPW and left ventricular hypertrophy carried a known pathogenic variant in MYH7. We found rare de novo variants in genes associated with arrhythmia and cardiomyopathy (ANK2, NEBL, PITX2, and PRDM16) in this cohort. There was an increased burden of rare deleterious variants (MAF <= 0.005) with CADD score >= 25 in genes linked to AF in cases compared to controls (P = .0023).

CONCLUSIONS: Our findings show an increased burden of rare deleterious variants in genes linked to AF in WPW syndrome, suggesting that genetic factors that determine the development of accessory pathways may be linked to an increased susceptibility of atrial muscle to AF in a subset of patients.

}, keywords = {Adolescent, Adult, AMP-Activated Protein Kinases, Ankyrins, Atrial Fibrillation, Carrier Proteins, Child, Cohort Studies, Cytoskeletal Proteins, DNA-Binding Proteins, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heart Atria, Homeodomain Proteins, Humans, LIM Domain Proteins, Male, Mutation, Transcription Factors, Whole Exome Sequencing, Wolff-Parkinson-White Syndrome, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61571}, author = {Coban-Akdemir, Zeynep H and Charng, Wu-Lin and Azamian, Mahshid and Paine, Ingrid S and Punetha, Jaya and Grochowski, Christopher M and Gambin, Tomasz and Valdes, Santiago O and Cannon, Bryan and Zapata, Gladys and Hernandez, Patricia P and Jhangiani, Shalini and Doddapaneni, Harsha and Hu, Jianhong and Boricha, Fatima and Muzny, Donna M and Boerwinkle, Eric and Yang, Yaping and Gibbs, Richard A and Posey, Jennifer E and Wehrens, Xander H T and Belmont, John W and Kim, Jeffrey J and Miyake, Christina Y and Lupski, James R and Lalani, Seema R} } @article {710, title = {X-chromosome association studies of congenital heart defects.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 01}, pages = {250-254}, keywords = {Chromosome Deletion, Chromosomes, Human, X, Female, Genes, X-Linked, Genetic Association Studies, Genetic Predisposition to Disease, Heart Defects, Congenital, Humans, Male}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61411}, author = {Agopian, A J and Hoang, Thanh T and Goldmuntz, Elizabeth and Hakonarson, Hakon and Musfee, Fadi I and Mitchell, Laura E} } @article {720, title = {Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 01}, pages = {150-168}, abstract = {

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM$\#$ 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridization~and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65\%) and the clustering of ~47\% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.

}, keywords = {Child, Child, Preschool, Chromosome Breakpoints, Chromosome Deletion, Chromosome Mapping, Chromosomes, Human, X, Comparative Genomic Hybridization, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Nervous System Diseases, Pedigree, Phenotype, Quantitative Trait, Heritable, Repetitive Sequences, Nucleic Acid, Sex Factors, Syndrome, X Chromosome Inactivation}, issn = {1098-1004}, doi = {10.1002/humu.23902}, author = {Hijazi, Hadia and Coelho, Fernanda S and Gonzaga-Jauregui, Claudia and Bernardini, Laura and Mar, Soe S and Manning, Melanie A and Hanson-Kahn, Andrea and Naidu, Sakkubai and Srivastava, Siddharth and Lee, Jennifer A and Jones, Julie R and Friez, Michael J and Alberico, Thomas and Torres, Barbara and Fang, Ping and Cheung, Sau Wai and Song, Xiaofei and Davis-Williams, Angelique and Jornlin, Carly and Wight, Patricia A and Patyal, Pankaj and Taube, Jennifer and Poretti, Andrea and Inoue, Ken and Zhang, Feng and Pehlivan, Davut and Carvalho, Claudia M B and Hobson, Grace M and Lupski, James R} } @article {703, title = {COL4A1 mutations as a potential novel cause of autosomal dominant CAKUT in humans.}, journal = {Hum Genet}, volume = {138}, year = {2019}, month = {2019 Oct}, pages = {1105-1115}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45\%) that manifests before 30~years of age. The genetic locus containing COL4A1 (13q33-34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n = 257) and with nephrotic syndrome (NS) due to monogenic causes (n = 100). We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4\% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.

}, keywords = {Alleles, Amino Acid Substitution, Collagen Type IV, Computational Biology, Congenital Abnormalities, Databases, Genetic, DNA Mutational Analysis, Evolution, Molecular, Female, Genetic Association Studies, Genetic Loci, Genomics, Heterozygote, Humans, Kidney, Kidney Diseases, Cystic, Male, Mutation, Nephrotic Syndrome, Phenotype, Urinary Tract, Web Browser, Whole Exome Sequencing}, issn = {1432-1203}, doi = {10.1007/s00439-019-02042-4}, author = {Kitzler, Thomas M and Schneider, Ronen and Kohl, Stefan and Kolvenbach, Caroline M and Connaughton, Dervla M and Dai, Rufeng and Mann, Nina and Nakayama, Makiko and Majmundar, Amar J and Wu, Chen-Han W and Kari, Jameela A and El Desoky, Sherif M and Senguttuvan, Prabha and Bogdanovic, Radovan and Staji{\'c}, Natasa and Valivullah, Zaheer and Lek, Monkol and Mane, Shrikant and Lifton, Richard P and Tasic, Velibor and Shril, Shirlee and Hildebrandt, Friedhelm} } @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 {614, title = {Analysis of 17 genes detects mutations in 81\% of 811 patients with lissencephaly.}, journal = {Genet Med}, volume = {20}, year = {2018}, month = {2018 11}, pages = {1354-1364}, abstract = {

PURPOSE: To estimate diagnostic yield and genotype-phenotype correlations in a cohort of 811 patients with lissencephaly or subcortical band heterotopia.

METHODS: We collected DNA from 756 children with lissencephaly over 30 years. Many were tested for deletion 17p13.3 and mutations of LIS1, DCX, and ARX, but few other genes. Among those tested, 216 remained unsolved and were tested by a targeted panel of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) or by whole-exome sequencing. Fifty-five patients studied at another institution were added as a validation cohort.

RESULTS: The overall mutation frequency in the entire cohort was 81\%. LIS1 accounted for 40\% of patients, followed by DCX (23\%), TUBA1A (5\%), and DYNC1H1 (3\%). Other genes accounted for 1\% or less of patients. Nineteen percent remained unsolved, which suggests that several additional genes remain to be discovered. The majority of unsolved patients had posterior pachygyria, subcortical band heterotopia, or mild frontal pachygyria.

CONCLUSION: The brain-imaging pattern correlates with mutations in single lissencephaly-associated genes, as well as in biological pathways. We propose the first LIS classification system based on the underlying molecular mechanisms.

}, keywords = {Brain, Classical Lissencephalies and Subcortical Band Heterotopias, DNA Mutational Analysis, Female, Genetic Association Studies, Humans, Lissencephaly, Male, Mutation, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/gim.2018.8}, author = {Di Donato, Nataliya and Timms, Andrew E and Aldinger, Kimberly A and Mirzaa, Ghayda M and Bennett, James T and Collins, Sarah and Olds, Carissa and Mei, Davide and Chiari, Sara and Carvill, Gemma and Myers, Candace T and Rivi{\`e}re, Jean-Baptiste and Zaki, Maha S and Gleeson, Joseph G and Rump, Andreas and Conti, Valerio and Parrini, Elena and Ross, M Elizabeth and Ledbetter, David H and Guerrini, Renzo and Dobyns, William B} } @article {466, title = {A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis.}, journal = {Am J Med Genet A}, volume = {176}, year = {2018}, month = {2018 04}, pages = {1015-1022}, abstract = {

Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common craniofacial abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with TA. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.

}, keywords = {Alleles, Amino Acid Substitution, Animals, Anodontia, Child, Consanguinity, Facies, Genetic Association Studies, Genotype, Humans, Male, Mice, Mutation, Neoplasm Proteins, Pedigree, Phenotype, Radiography, Receptors, Cell Surface, Whole Exome Sequencing}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38625}, author = {Dinckan, Nuriye and Du, Renqian and Akdemir, Zeynep C and Bayram, Yavuz and Jhangiani, Shalini N and Doddapaneni, Harsha and Hu, Jianhong and Muzny, Donna M and Guven, Yeliz and Aktoren, Oya and Kayserili, H{\"u}lya and Boerwinkle, Eric and Gibbs, Richard A and Posey, Jennifer E and Lupski, James R and Uyguner, Zehra O and Letra, Ariadne} } @article {512, title = {Confirmation of the Role of DHX38 in the Etiology of Early-Onset Retinitis Pigmentosa.}, journal = {Invest Ophthalmol Vis Sci}, volume = {59}, year = {2018}, month = {2018 09 04}, pages = {4552-4557}, abstract = {

Purpose: Retinitis pigmentosa (RP) is a genetically heterogeneous trait with autosomal-recessive (ar) inheritance underlying 50\% of genetic disease cases. Sixty-one arRP genes have been identified, and recently, DHX38 has been reported as a potential candidate gene for arRP with only a single family reported with a variant of unknown significance. We identified a missense variant in DHX38 that co-segregates with the arRP phenotype in two Pakistani families confirming the involvement of DHX38 in the etiology of early-onset RP.

Methods: Exome sequencing was performed using two DNA samples from affected members of Pakistani families (MA88 and MA157) with early onset arRP. Sanger sequencing of DNA samples from all family members confirmed the segregation of candidate variant within both families.

Results: A novel missense DHX38 variant c.971G>A; p.(Arg324Gln) was identified which segregates with the arRP phenotype and yielded a logarithm of the odds (LOD) score of 5.0 and 4.3 for families MA88 and MA157, respectively. This variant is predicted to be conserved and deleterious by several bioinformatics tools.

Conclusions: We identified a second deleterious DHX38 variant that segregates with arRP in two families, providing additional evidence that DHX38 is involved in RP etiology. DHX38 encodes for pre-mRNA splicing factor PRP16, which is important in catalyzing pre-mRNA splicing.

}, keywords = {Adolescent, Adult, Cataract, Computational Biology, DEAD-box RNA Helicases, Female, Genes, Recessive, Genetic Association Studies, Genetic Linkage, Humans, Male, Mutation, Missense, Nucleotide Mapping, Ophthalmoscopy, Pedigree, Retinitis Pigmentosa, RNA Splicing Factors, Sequence Analysis, DNA, Whole Exome Sequencing, Young Adult}, issn = {1552-5783}, doi = {10.1167/iovs.18-23849}, author = {Latif, Zahid and Chakchouk, Imen and Schrauwen, Isabelle and Lee, Kwanghyuk and Santos-Cortez, Regie Lyn P and Abbe, Izoduwa and Acharya, Anushree and Jarral, Afeefa and Ali, Imran and Ullah, Ehsan and Khan, Muhammad Nasim and Ali, Ghazanfar and Tahir, Tufail Hussain and Bamshad, Michael J and Nickerson, Deborah A and Ahmad, Wasim and Ansar, Muhammad and Leal, Suzanne M} } @article {538, title = {Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies.}, journal = {Hum Mutat}, volume = {39}, year = {2018}, month = {2018 01}, pages = {152-166}, abstract = {

Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis-van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.

}, keywords = {Ciliopathies, Cytoplasmic Dyneins, Genetic Association Studies, Genetic Markers, Genetic Variation, Genotype, Humans, Mutation, Phenotype, Proteins, Radiography, Skeleton, Whole Exome Sequencing}, issn = {1098-1004}, doi = {10.1002/humu.23362}, author = {Zhang, Wenjuan and Taylor, S Paige and Ennis, Hayley A and Forlenza, Kimberly N and Duran, Ivan and Li, Bing and Sanchez, Jorge A Ortiz and Nevarez, Lisette and Nickerson, Deborah A and Bamshad, Michael and Lachman, Ralph S and Krakow, Deborah and Cohn, Daniel H} } @article {542, title = {Genotype-phenotype investigation of 35 patients from 11 unrelated families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome.}, journal = {Mol Genet Genomic Med}, volume = {6}, year = {2018}, month = {2018 03}, pages = {230-248}, abstract = {

BACKGROUND: The camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by camptodactyly, noninflammatory arthropathy, coxa vara, and pericarditis. CACP is caused by mutations in the proteoglycan 4 (PRG4) gene, which encodes a lubricating glycoprotein present in the synovial fluid and at the surface of articular cartilage.

METHODS: In the present study, we compared the clinical and molecular findings of CACP syndrome in 35 patients from 11 unrelated families. In 28 patients, whole exome sequencing was used to investigate genomic variations.

RESULTS: We found that camptodactyly of hands was the first symptom presented by most patients. Swelling of wrists, knees, and elbows began before 4~years of age, while the age of joint involvement was variable. Patients reported an increased pain level after the age of 10, and severe hip involvement developed after 20~years old. All patients presented developmental coxa vara and seven patients (~22\%) had pleural effusion, pericarditis, and/or ascites. We identified nine novel genomic alterations, including the first case of homozygous complete deletion of exon 1 in the PRG4 gene.

CONCLUSION: With this study, we contribute to the catalog of CACP causing variants. We confirm that the skeletal component of this disease worsens with age, and presents the potential mechanisms for interfamily variability, by discussing the influence of a modifier gene and escape from nonsense-mediated mRNA decay. We believe that this report will increase awareness of this familial arthropathic condition and the characteristic clinical and radiological findings will facilitate the differentiation from the common childhood rheumatic diseases such as juvenile idiopathic arthritis.

}, keywords = {Adolescent, Adult, Arthropathy, Neurogenic, Child, Child, Preschool, Coxa Vara, Exons, Female, Genetic Association Studies, Hand Deformities, Congenital, Humans, Male, Middle Aged, Mutation, Proteoglycans, Retrospective Studies, Sequence Deletion, Synovitis, Whole Exome Sequencing}, issn = {2324-9269}, doi = {10.1002/mgg3.364}, author = {Yilmaz, Saliha and Uluda{\u g} Alkaya, Dilek and Kasapcopur, Ozgur and Barut, Kenan and Akdemir, Ekin S and Celen, Cemre and Youngblood, Mark W and Yasuno, Katsuhito and Bilguvar, Kaya and G{\"u}nel, Murat and Tuysuz, Beyhan} } @article {494, title = {A homozygous founder mutation in associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features.}, journal = {J Med Genet}, volume = {55}, year = {2018}, month = {2018 01}, pages = {48-54}, abstract = {

BACKGROUND: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain.

OBJECTIVE: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families.

METHODS: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease.

RESULTS: We identified six individuals from three unrelated families with a founder homozygous splice mutation in , encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold.

CONCLUSION: This study provides clinical and functional evidence of the role of in brain development and function.

}, keywords = {Animals, Autistic Disorder, Epilepsy, Founder Effect, Genetic Association Studies, Homozygote, Humans, Microcephaly, Mutation, Neurodevelopmental Disorders, Phenotype, Vesicular Transport Proteins, Zebrafish}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2017-104627}, author = {Marin-Valencia, Isaac and Novarino, Gaia and Johansen, Anide and Rosti, Basak and Issa, Mahmoud Y and Musaev, Damir and Bhat, Gifty and Scott, Eric and Silhavy, Jennifer L and Stanley, Valentina and Rosti, Rasim O and Gleeson, Jeremy W and Imam, Farhad B and Zaki, Maha S and Gleeson, Joseph G} } @article {383, title = {Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively.}, journal = {Genet Med}, volume = {20}, year = {2018}, month = {2018 04}, pages = {411-419}, abstract = {

PurposeOsteogenesis imperfecta (OI) is a heritable skeletal dysplasia. Dominant pathogenic variants in COL1A1 and COL1A2 explain the majority of OI cases. At least 15 additional genes have been identified, but those still do not account for all OI phenotypes that present. We sought the genetic cause of mild and lethal OI phenotypes in an unsolved family.MethodsWe performed exome sequencing on seven members of the family, both affected and unaffected.ResultsWe identified a variant in cyclic AMP responsive element binding protein 3-like 1 (CREB3L1) in a consanguineous family. The variant caused a prenatal/perinatal lethal OI in homozygotes, similar to that seen in OI type II as a result of mutations in type I collagen genes, and a mild phenotype (fractures, blue sclerae) in multiple heterozygous family members. CREB3L1 encodes old astrocyte specifically induced substance (OASIS), an endoplasmic reticulum stress transducer. The variant disrupts a DNA-binding site and prevents OASIS from acting on its transcriptional targets including SEC24D, which encodes a component of the coat protein II complex.ConclusionThis report confirms that CREB3L1 is an OI-related gene and suggests the pathogenic mechanism of CREB3L1-associated OI involves the altered regulation of proteins involved in cellular secretion.

}, keywords = {Alleles, Amino Acid Sequence, Collagen Type I, Cyclic AMP Response Element-Binding Protein, DNA Mutational Analysis, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Mutation, Nerve Tissue Proteins, Osteogenesis Imperfecta, Pedigree, Phenotype, Radiography, Sequence Analysis, DNA, Severity of Illness Index, Ultrasonography, Prenatal}, issn = {1530-0366}, doi = {10.1038/gim.2017.115}, author = {Keller, Rachel B and Tran, Thao T and Pyott, Shawna M and Pepin, Melanie G and Savarirayan, Ravi and McGillivray, George and Nickerson, Deborah A and Bamshad, Michael J and Byers, Peter H} } @article {522, title = {Whole exome sequencing analysis in severe chronic obstructive pulmonary disease.}, journal = {Hum Mol Genet}, volume = {27}, year = {2018}, month = {2018 11 01}, pages = {3801-3812}, abstract = {

Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is substantially influenced by genetic factors. Alpha-1 antitrypsin deficiency demonstrates that rare coding variants of large effect can influence COPD susceptibility. To identify additional rare coding variants in patients with severe COPD, we conducted whole exome sequencing analysis in 2543 subjects from two family-based studies (Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene). Applying a gene-based segregation test in the family-based data, we identified significant segregation of rare loss of function variants in TBC1D10A and RFPL1 (P-value~<~2x10-6), but were unable to find similar variants in the case-control study. In single-variant, gene-based and pathway association analyses, we were unable to find significant findings that replicated or were significant in meta-analysis. However, we found that the top results in the two datasets were in proximity to each other in the protein-protein interaction network (P-value~=~0.014), suggesting enrichment of these results for similar biological processes. A network of these association results and their neighbors was significantly enriched in the transforming growth factor beta-receptor binding and cilia-related pathways. Finally, in a more detailed examination of candidate genes, we identified individuals with putative high-risk variants, including patients harboring homozygous mutations in genes associated with cutis laxa and Niemann-Pick Disease Type C. Our results likely reflect heterogeneity of genetic risk for COPD along with limitations of statistical power and functional annotation, and highlight the potential of network analysis to gain insight into genetic association studies.

}, keywords = {Adolescent, Adult, Aged, Case-Control Studies, DNA Mutational Analysis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Whole Exome Sequencing, Young Adult}, issn = {1460-2083}, doi = {10.1093/hmg/ddy269}, author = {Qiao, Dandi and Ameli, Asher and Prokopenko, Dmitry and Chen, Han and Kho, Alvin T and Parker, Margaret M and Morrow, Jarrett and Hobbs, Brian D and Liu, Yanhong and Beaty, Terri H and Crapo, James D and Barnes, Kathleen C and Nickerson, Deborah A and Bamshad, Michael and Hersh, Craig P and Lomas, David A and Agusti, Alvar and Make, Barry J and Calverley, Peter M A and Donner, Claudio F and Wouters, Emiel F and Vestbo, J{\o}rgen and Par{\'e}, Peter D and Levy, Robert D and Rennard, Stephen I and Tal-Singer, Ruth and Spitz, Margaret R and Sharma, Amitabh and Ruczinski, Ingo and Lange, Christoph and Silverman, Edwin K and Cho, Michael H} } @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 {497, title = {Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43\% of 35 Families With Midaortic Syndrome.}, journal = {Hypertension}, volume = {71}, year = {2018}, month = {2018 04}, pages = {691-699}, abstract = {

Midaortic syndrome (MAS) is a rare cause of severe childhood hypertension characterized by narrowing of the abdominal aorta in children and is associated with extensive vascular disease. It may occur as part of a genetic syndrome, such as neurofibromatosis, or as consequence of a pathological inflammatory disease. However, most cases are considered idiopathic. We hypothesized that in a high percentage of these patients, a monogenic cause of disease may be detected by evaluating whole exome sequencing data for mutations in 1 of 38 candidate genes previously described to cause vasculopathy. We studied a cohort of 36 individuals from 35 different families with MAS by exome sequencing. In 15 of 35 families (42.9\%), we detected likely causal dominant mutations. In 15 of 35 (42.9\%) families with MAS, whole exome sequencing revealed a mutation in one of the genes previously associated with vascular disease (, , , , and ). Ten of the 15 mutations have not previously been reported. This is the first report of , , or mutations in individuals with MAS. Mutations were detected in (6/15 families), (4/15 families), (3/15 families), and one family each for and Eight individuals had syndromic disease and 7 individuals had isolated MAS. Whole exome sequencing can provide conclusive molecular genetic diagnosis in a high fraction of individuals with syndromic or isolated MAS. Establishing an etiologic diagnosis may reveal genotype/phenotype correlations for MAS in the future and should, therefore, be performed routinely in MAS.

}, keywords = {Adolescent, Aorta, Abdominal, Aortic Valve Stenosis, Child, Child, Preschool, Cohort Studies, Female, Genetic Association Studies, Humans, Hypertension, Jagged-1 Protein, Male, Mutation, Neurofibromatoses, Neurofibromin 1, Pedigree, Syndrome, United States, Whole Exome Sequencing}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.117.10296}, author = {Warejko, Jillian K and Schueler, Markus and Vivante, Asaf and Tan, Weizhen and Daga, Ankana and Lawson, Jennifer A and Braun, Daniela A and Shril, Shirlee and Amann, Kassaundra and Somers, Michael J G and Rodig, Nancy M and Baum, Michelle A and Daouk, Ghaleb and Traum, Avram Z and Kim, Heung Bae and Vakili, Khashayar and Porras, Diego and Lock, James and Rivkin, Michael J and Chaudry, Gulraiz and Smoot, Leslie B and Singh, Michael N and Smith, Edward R and Mane, Shrikant M and Lifton, Richard P and Stein, Deborah R and Ferguson, Michael A and Hildebrandt, Friedhelm} } @article {446, title = {WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 01 04}, pages = {27-43}, abstract = {

Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, \~{}70\% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.

}, keywords = {Adolescent, Adult, Base Sequence, Child, Child, Preschool, Chromosome Segregation, Craniofacial Abnormalities, Diagnosis, Differential, Dwarfism, Female, Genes, Dominant, Genetic Association Studies, Genetic Heterogeneity, Humans, Limb Deformities, Congenital, Male, Middle Aged, Mutation, Missense, Phenotype, Urogenital Abnormalities, Wnt Signaling Pathway}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.10.002}, author = {White, Janson J and Mazzeu, Juliana F and Coban-Akdemir, Zeynep and Bayram, Yavuz and Bahrambeigi, Vahid and Hoischen, Alexander and van Bon, Bregje W M and Gezdirici, Alper and Gulec, Elif Yilmaz and Ramond, Francis and Touraine, Renaud and Thevenon, Julien and Shinawi, Marwan and Beaver, Erin and Heeley, Jennifer and Hoover-Fong, Julie and Durmaz, Ceren D and Karabulut, Halil Gurhan and Marzioglu-Ozdemir, Ebru and Cayir, Atilla and Duz, Mehmet B and Seven, Mehmet and Price, Susan and Ferreira, Barbara Merfort and Vianna-Morgante, Angela M and Ellard, Sian and Parrish, Andrew and Stals, Karen and Flores-Daboub, Josue and Jhangiani, Shalini N and Gibbs, Richard A and Brunner, Han G and Sutton, V Reid and Lupski, James R and Carvalho, Claudia M B} } @article {443, title = {Complex phenotypes associated with STIM1 mutations in both coiled coil and EF-hand domains.}, journal = {Neuromuscul Disord}, volume = {27}, year = {2017}, month = {2017 Sep}, pages = {861-872}, abstract = {

Dominant mutations in STIM1 are a cause of three allelic conditions: tubular aggregate myopathy, Stormorken syndrome (a complex phenotype including myopathy, hyposplenism, hypocalcaemia and bleeding diathesis), and a platelet dysfunction disorder, York platelet syndrome. Previous reports have suggested a genotype-phenotype correlation with mutations in the N-terminal EF-hand domain associated with tubular aggregate myopathy, and a common mutation at p.R304W in a coiled coil domain associated with Stormorken syndrome. In this study individuals with STIM1 variants were identified by exome sequencing or STIM1 direct sequencing, and assessed for neuromuscular, haematological and biochemical evidence of the allelic disorders of STIM1. STIM1 mutations were investigated by fibroblast calcium imaging and 3D modelling. Six individuals with STIM1 mutations, including two novel mutations (c.262A>G (p.S88G) and c.911G>A (p.R304Q)), were identified. Extra-neuromuscular symptoms including thrombocytopenia, platelet dysfunction, hypocalcaemia or hyposplenism were present in 5/6 patients with mutations in both the EF-hand and CC domains. 3/6 patients had psychiatric disorders, not previously reported in STIM1 disease. Review of published STIM1 patients (n = 49) confirmed that neuromuscular symptoms are present in most patients. We conclude that the phenotype associated with activating STIM1 mutations frequently includes extra-neuromuscular features such as hypocalcaemia, hypo-/asplenia and platelet dysfunction regardless of mutation domain.

}, keywords = {Adult, Blood Platelet Disorders, Calcium, Cell Culture Techniques, DNA Mutational Analysis, Dyslexia, Erythrocytes, Abnormal, Family Health, Female, Fibroblasts, Genetic Association Studies, Humans, Ichthyosis, Magnetic Resonance Imaging, Male, Microscopy, Electron, Middle Aged, Migraine Disorders, Miosis, Models, Molecular, Muscle Fatigue, Muscle, Skeletal, Mutation, Myopathies, Structural, Congenital, NAD, Neoplasm Proteins, Spleen, Stromal Interaction Molecule 1}, issn = {1873-2364}, doi = {10.1016/j.nmd.2017.05.002}, author = {Harris, Elizabeth and Burki, Umar and Marini-Bettolo, Chiara and Neri, Marcella and Scotton, Chiara and Hudson, Judith and Bertoli, Marta and Evangelista, Teresinha and Vroling, Bas and Polvikoski, Tuomo and Roberts, Mark and Topf, Ana and Bushby, Kate and McArthur, Daniel and Lochm{\"u}ller, Hanns and Ferlini, Alessandra and Straub, Volker and Barresi, Rita} } @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 {411, title = {denovo-db: a compendium of human de novo variants.}, journal = {Nucleic Acids Res}, volume = {45}, year = {2017}, month = {2017 01 04}, pages = {D804-D811}, abstract = {

Whole-exome and whole-genome sequencing have facilitated the large-scale discovery of de novo variants in human disease. To date, most de novo discovery through next-generation sequencing focused on congenital heart disease and neurodevelopmental disorders (NDDs). Currently, de novo variants are one of the most significant risk factors for NDDs with a substantial overlap of genes involved in more than one NDD. To facilitate better usage of published data, provide standardization of annotation, and improve accessibility, we created denovo-db (http://denovo-db.gs.washington.edu), a database for human de novo variants. As of July 2016, denovo-db contained 40 different studies and 32,991 de novo variants from 23,098 trios. Database features include basic variant information (chromosome location, change, type); detailed annotation at the transcript and protein levels; severity scores; frequency; validation status; and, most importantly, the phenotype of the individual with the variant. We included a feature on our browsable website to download any query result, including a downloadable file of the full database with additional variant details. denovo-db provides necessary information for researchers to compare their data to other individuals with the same phenotype and also to controls allowing for a better understanding of the biology of de novo variants and their contribution to disease.

}, keywords = {Computational Biology, Databases, Nucleic Acid, Genetic Association Studies, Genetic Variation, Germ-Line Mutation, Humans, Molecular Sequence Annotation, Polymorphism, Single Nucleotide, Web Browser}, issn = {1362-4962}, doi = {10.1093/nar/gkw865}, author = {Turner, Tychele N and Yi, Qian and Krumm, Niklas and Huddleston, John and Hoekzema, Kendra and F Stessman, Holly A and Doebley, Anna-Lisa and Bernier, Raphael A and Nickerson, Deborah A and Eichler, Evan E} } @article {366, title = {Efficient CNV breakpoint analysis reveals unexpected structural complexity and correlation of dosage-sensitive genes with clinical severity in genomic disorders.}, journal = {Hum Mol Genet}, volume = {26}, year = {2017}, month = {2017 05 15}, pages = {1927-1941}, abstract = {

Genomic disorders are the clinical conditions manifested by submicroscopic genomic rearrangements including copy number variants (CNVs). The CNVs can be identified by array-based comparative genomic hybridization (aCGH), the most commonly used technology for molecular diagnostics of genomic disorders. However, clinical aCGH only informs CNVs in the probe-interrogated regions. Neither orientational information nor the resulting genomic rearrangement structure is provided, which is a key to uncovering mutational and pathogenic mechanisms underlying genomic disorders. Long-range polymerase chain reaction (PCR) is a traditional approach to obtain CNV breakpoint junction, but this method is inefficient when challenged by structural complexity such as often found at the PLP1 locus in association with Pelizaeus-Merzbacher disease (PMD). Here we introduced {\textquoteright}capture and single-molecule real-time sequencing{\textquoteright} (cap-SMRT-seq) and newly developed {\textquoteright}asymmetry linker-mediated nested PCR walking{\textquoteright} (ALN-walking) for CNV breakpoint sequencing in 49 subjects with PMD-associated CNVs. Remarkably, 29 (94\%) of the 31 CNV breakpoint junctions unobtainable by conventional long-range PCR were resolved by cap-SMRT-seq and ALN-walking. Notably, unexpected CNV complexities, including inter-chromosomal rearrangements that cannot be resolved by aCGH, were revealed by efficient breakpoint sequencing. These sequence-based structures of PMD-associated CNVs further support the role of DNA replicative mechanisms in CNV mutagenesis, and facilitate genotype-phenotype correlation studies. Intriguingly, the lengths of gained segments by CNVs are strongly correlated with clinical severity in PMD, potentially reflecting the functional contribution of other dosage-sensitive genes besides PLP1. Our study provides new efficient experimental approaches (especially ALN-walking) for CNV breakpoint sequencing and highlights their importance in uncovering CNV mutagenesis and pathogenesis in genomic disorders.

}, keywords = {Base Sequence, Comparative Genomic Hybridization, DNA Copy Number Variations, DNA Replication, Female, Gene Dosage, Gene Duplication, Gene Rearrangement, Genetic Association Studies, Genome, Human, Genomics, Humans, Male, Mutation, Pelizaeus-Merzbacher Disease, Sequence Analysis, DNA}, issn = {1460-2083}, doi = {10.1093/hmg/ddx102}, author = {Zhang, Ling and Wang, Jingmin and Zhang, Cheng and Li, Dongxiao and Carvalho, Claudia M B and Ji, Haoran and Xiao, Jianqiu and Wu, Ye and Zhou, Weichen and Wang, Hongyan and Jin, Li and Luo, Yang and Wu, Xiru and Lupski, James R and Zhang, Feng and Jiang, Yuwu} } @article {428, title = {"Matching" consent to purpose: The example of the Matchmaker Exchange.}, journal = {Hum Mutat}, volume = {38}, year = {2017}, month = {2017 10}, pages = {1281-1285}, abstract = {

The Matchmaker Exchange (MME) connects rare disease clinicians and researchers to facilitate the sharing of data from undiagnosed patients for the purpose of novel gene discovery. Such sharing raises the odds that two or more similar patients with candidate genes in common may be found, thereby allowing their condition to be more readily studied and understood. Consent considerations for data sharing in MME included both the ethical and legal differences between clinical and research settings and the level of privacy risk involved in sharing varying amounts of rare disease patient data to enable patient matches. In this commentary, we discuss these consent considerations and the resulting MME Consent Policy as they may be relevant to other international data sharing initiatives.

}, keywords = {Databases, Genetic, Genetic Association Studies, Genetic Diseases, Inborn, Genomics, Humans, Information Dissemination, Patient Selection, Physicians, Rare Diseases, Research Personnel, Translational Medical Research}, issn = {1098-1004}, doi = {10.1002/humu.23278}, author = {Dyke, Stephanie O M and Knoppers, Bartha M and Hamosh, Ada and Firth, Helen V and Hurles, Matthew and Brudno, Michael and Boycott, Kym M and Philippakis, Anthony A and Rehm, Heidi L} } @article {440, title = {Matchmaker Exchange.}, journal = {Curr Protoc Hum Genet}, volume = {95}, year = {2017}, month = {2017 10 18}, pages = {9.31.1-9.31.15}, abstract = {

In well over half of the individuals with rare disease who undergo clinical or research next-generation sequencing, the responsible gene cannot be determined. Some reasons for this relatively low yield include unappreciated phenotypic heterogeneity; locus heterogeneity; somatic and germline mosaicism; variants of uncertain functional significance; technically inaccessible areas of the genome; incorrect mode of inheritance investigated; and inadequate communication between clinicians and basic scientists with knowledge of particular genes, proteins, or biological systems. To facilitate such communication and improve the search for patients or model organisms with similar phenotypes and variants in specific candidate genes, we have developed the Matchmaker Exchange (MME). MME was created to establish a federated network connecting databases of genomic and phenotypic data using a common application programming interface (API). To date, seven databases can exchange data using the API (GeneMatcher, PhenomeCentral, DECIPHER, MyGene2, matchbox, Australian Genomics Health Alliance Patient Archive, and Monarch Initiative; the latter included for model organism matching). This article guides usage of the MME for rare disease gene discovery. {\textcopyright} 2017 by John Wiley \& Sons, Inc.

}, keywords = {Animals, Computational Biology, Databases, Genetic, Genetic Association Studies, Genetic Predisposition to Disease, Genomics, Humans, Rare Diseases, Software, Web Browser}, issn = {1934-8258}, doi = {10.1002/cphg.50}, author = {Sobreira, Nara L M and Arachchi, Harindra and Buske, Orion J and Chong, Jessica X and Hutton, Ben and Foreman, Julia and Schiettecatte, Fran{\c c}ois and Groza, Tudor and Jacobsen, Julius O B and Haendel, Melissa A and Boycott, Kym M and Hamosh, Ada and Rehm, Heidi L} } @article {387, title = {Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Aug}, abstract = {

BACKGROUND: Left ventricular noncompaction (LVNC) is a genetically and phenotypically heterogeneous disease and, although increasingly recognized in clinical practice, there is a lack of widely accepted diagnostic criteria. We sought to identify novel genetic causes of LVNC and describe genotype-phenotype correlations.

METHODS AND RESULTS: A total of 190 patients from 174 families with left ventricular hypertrabeculation (LVHT) or LVNC were referred for cardiac magnetic resonance and whole-exome sequencing. A total of 425 control individuals were included to identify variants of interest (VOIs). We found an excess of 138 VOIs in 102 (59\%) unrelated patients in 54 previously identified LVNC or other known cardiomyopathy genes. VOIs were found in 68 of 90 probands with LVNC and 34 of 84 probands with LVHT (76\% and 40\%, respectively; <0.001). We identified 0, 1, and >=2 VOIs in 72, 74, and 28 probands, respectively. We found increasing number of VOIs in a patient strongly correlated with several markers of disease severity, including ratio of noncompacted to compacted myocardium (<0.001) and left ventricular ejection fraction (=0.01). The presence of sarcomeric gene mutations was associated with increased occurrence of late gadolinium enhancement (=0.004).

CONCLUSIONS: LVHT and LVNC likely represent a continuum of genotypic disease with differences in severity and variable phenotype explained, in part, by the number of VOIs and whether mutations are present in sarcomeric or nonsarcomeric genes. Presence of VOIs is common in patients with LVHT. Our findings expand the current clinical and genetic diagnostic approaches for patients with LVHT and LVNC.

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Cardiac Myosins, Carrier Proteins, Child, Connectin, Female, Genetic Association Studies, Genetic Variation, Heart Ventricles, Humans, LIM Domain Proteins, Magnetic Resonance Imaging, Cine, Male, Middle Aged, Muscle Proteins, Myocardium, Myosin Heavy Chains, Prospective Studies, Severity of Illness Index, Tropomyosin, Ventricular Dysfunction, Left, Young Adult}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.117.001763}, author = {Miszalski-Jamka, Karol and Jefferies, John L and Mazur, Wojciech and G{\l}owacki, Jan and Hu, Jianhong and Lazar, Monika and Gibbs, Richard A and Liczko, Jacek and K{\l}y{\'s}, Jan and Venner, Eric and Muzny, Donna M and Rycaj, Jaros{\l}aw and Bia{\l}kowski, Jacek and Kluczewska, Ewa and Kalarus, Zbigniew and Jhangiani, Shalini and Al-Khalidi, Hussein and Kukulski, Tomasz and Lupski, James R and Craigen, William J and Bainbridge, Matthew N} } @article {7, title = {Whole-Genome Sequencing of Cytogenetically Balanced Chromosome Translocations Identifies Potentially Pathological Gene Disruptions and Highlights the Importance of Microhomology in the Mechanism of Formation.}, journal = {Hum Mutat}, volume = {38}, year = {2017}, month = {2017 Feb}, pages = {180-192}, abstract = {

Most balanced translocations are thought to result mechanistically from nonhomologous end joining or, in rare cases of recurrent events, by nonallelic homologous recombination. Here, we use low-coverage mate pair whole-genome sequencing to fine map rearrangement breakpoint junctions in both phenotypically normal and affected translocation carriers. In total, 46 junctions from 22 carriers of balanced translocations were characterized. Genes were disrupted in 48\% of the breakpoints; recessive genes in four normal carriers and known dominant intellectual disability genes in three affected carriers. Finally, seven candidate disease genes were disrupted in five carriers with neurocognitive disabilities (SVOPL, SUSD1, TOX, NCALD, SLC4A10) and one XX-male carrier with Tourette syndrome (LYPD6, GPC5). Breakpoint junction analyses revealed microhomology and small templated insertions in a substantive fraction of the analyzed translocations (17.4\%; n = 4); an observation that was substantiated by reanalysis of 37 previously published translocation junctions. Microhomology associated with templated insertions is a characteristic seen in the breakpoint junctions of rearrangements mediated by error-prone replication-based repair mechanisms. Our data implicate that a mechanism involving template switching might contribute to the formation of at least 15\% of the interchromosomal translocation events.

}, keywords = {Base Sequence, Chromosome Breakage, Chromosome Mapping, Comparative Genomic Hybridization, DNA Copy Number Variations, Female, Genetic Association Studies, Genomics, Genotype, Homologous Recombination, Humans, In Situ Hybridization, Fluorescence, Karyotype, Male, Phenotype, Translocation, Genetic, Whole Genome Sequencing}, issn = {1098-1004}, doi = {10.1002/humu.23146}, author = {Nilsson, Daniel and Pettersson, Maria and Gustavsson, Peter and F{\"o}rster, Alisa and Hofmeister, Wolfgang and Wincent, Josephine and Zachariadis, Vasilios and Anderlid, Britt-Marie and Nordgren, Ann and M{\"a}kitie, Outi and Wirta, Valtteri and K{\"a}ller, Max and Vezzi, Francesco and Lupski, James R and Nordenskj{\"o}ld, Magnus and Lundberg, Elisabeth Syk and Carvalho, Claudia M B and Lindstrand, Anna} } @article {58, title = {Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism.}, journal = {JAMA Neurol}, volume = {73}, year = {2016}, month = {2016 07 01}, pages = {836-845}, abstract = {

IMPORTANCE: Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders are associated with significant childhood morbidity and mortality.

OBJECTIVE: To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly.

DESIGN, SETTING, AND PARTICIPANTS: Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children{\textquoteright}s Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase-AKT (serine/threonine kinase)-mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations.

MAIN OUTCOMES AND MEASURES: Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders.

RESULTS: Low-level mosaic mutations of MTOR were identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation of MTOR (p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation of MTOR (p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, all MTOR mutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size.

CONCLUSIONS AND RELEVANCE: In this study, mutations of MTOR were associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations of MTOR and pigmentary mosaicism in skin.

}, keywords = {Adolescent, Adult, Amino Acids, Animals, Cells, Cultured, Cerebral Cortex, Child, Child, Preschool, Developmental Disabilities, Embryo, Mammalian, Female, Gene Expression Regulation, Genetic Association Studies, Humans, Intercellular Signaling Peptides and Proteins, Male, Malformations of Cortical Development, Mechanistic Target of Rapamycin Complex 1, Megalencephaly, Mosaicism, Multiprotein Complexes, Mutation, Nerve Tissue Proteins, Neurons, Rats, Retrospective Studies, TOR Serine-Threonine Kinases, Young Adult}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2016.0363}, author = {Mirzaa, Ghayda M and Campbell, Catarina D and Solovieff, Nadia and Goold, Carleton and Jansen, Laura A and Menon, Suchithra and Timms, Andrew E and Conti, Valerio and Biag, Jonathan D and Adams, Carissa and Boyle, Evan August and Collins, Sarah and Ishak, Gisele and Poliachik, Sandra and Girisha, Katta M and Yeung, Kit San and Chung, Brian Hon Yin and Rahikkala, Elisa and Gunter, Sonya A and McDaniel, Sharon S and Macmurdo, Colleen Forsyth and Bernstein, Jonathan A and Martin, Beth and Leary, Rebecca and Mahan, Scott and Liu, Shanming and Weaver, Molly and Doerschner, Michael and Jhangiani, Shalini and Muzny, Donna M and Boerwinkle, Eric and Gibbs, Richard A and Lupski, James R and Shendure, Jay and Saneto, Russell P and Novotny, Edward J and Wilson, Christopher J and Sellers, William R and Morrissey, Michael and Hevner, Robert F and Ojemann, Jeffrey G and Guerrini, Renzo and Murphy, Leon O and Winckler, Wendy and Dobyns, William B} } @article {414, title = {De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 12}, pages = {1399-1409}, abstract = {

Intellectual disabilities are genetically heterogeneous and can be associated with congenital anomalies. Using whole-exome sequencing (WES), we identified five different de novo missense variants in the protein phosphatase-1 catalytic subunit beta (PPP1CB) gene in eight unrelated individuals who share an overlapping phenotype of dysmorphic features, macrocephaly, developmental delay or intellectual disability (ID), congenital heart disease, short stature, and skeletal and connective tissue abnormalities. Protein phosphatase-1 (PP1) is a serine/threonine-specific protein phosphatase involved in the dephosphorylation of a variety of proteins. The PPP1CB gene encodes a PP1 subunit that regulates the level of protein phosphorylation. All five altered amino acids we observed are highly conserved among the PP1 subunit family, and all are predicted to disrupt PP1 subunit binding and impair dephosphorylation. Our data suggest that our heterozygous de novo PPP1CB pathogenic variants are associated with syndromic intellectual disability.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Exome, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heart Defects, Congenital, Humans, Intellectual Disability, Male, Mutation, Missense, Phosphorylation, Protein Phosphatase 1}, issn = {1432-1203}, doi = {10.1007/s00439-016-1731-1}, author = {Ma, Lijiang and Bayram, Yavuz and McLaughlin, Heather M and Cho, Megan T and Krokosky, Alyson and Turner, Clesson E and Lindstrom, Kristin and Bupp, Caleb P and Mayberry, Katey and Mu, Weiyi and Bodurtha, Joann and Weinstein, Veronique and Zadeh, Neda and Alcaraz, Wendy and Powis, Z{\"o}e and Shao, Yunru and Scott, Daryl A and Lewis, Andrea M and White, Janson J and Jhangiani, Shalani N and Gulec, Elif Yilmaz and Lalani, Seema R and Lupski, James R and Retterer, Kyle and Schnur, Rhonda E and Wentzensen, Ingrid M and Bale, Sherri and Chung, Wendy K} } @article {533, title = {Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 Oct}, pages = {e1006335}, abstract = {

Left-ventricular outflow tract obstructions (LVOTO) encompass a wide spectrum of phenotypically heterogeneous heart malformations which frequently cluster in families. We performed family based whole-exome and targeted re-sequencing on 182 individuals from 51 families with multiple affected members. Central to our approach is the family unit which serves as a reference to identify causal genotype-phenotype correlations. Screening a multitude of 10 overlapping phenotypes revealed disease associated and co-segregating variants in 12 families. These rare or novel protein altering mutations cluster predominantly in genes (NOTCH1, ARHGAP31, MAML1, SMARCA4, JARID2, JAG1) along the Notch signaling cascade. This is in line with a significant enrichment (Wilcoxon, p< 0.05) of variants with a higher pathogenicity in the Notch signaling pathway in patients compared to controls. The significant enrichment of novel protein truncating and missense mutations in NOTCH1 highlights the allelic and phenotypic heterogeneity in our pediatric cohort. We identified novel co-segregating pathogenic mutations in NOTCH1 associated with left and right-sided cardiac malformations in three independent families with a total of 15 affected individuals. In summary, our results suggest that a small but highly pathogenic fraction of family specific mutations along the Notch cascade are a common cause of LVOTO.

}, keywords = {Aortic Valve, Codon, Nonsense, Constriction, Pathologic, Exome, Female, Genetic Association Studies, Genetic Linkage, Genome, Human, Heart Defects, Congenital, Humans, Male, Pedigree, Receptor, Notch1, Receptors, Notch, Sequence Deletion, Signal Transduction, Ventricular Outflow Obstruction}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006335}, author = {Preuss, Christoph and Capredon, Melanie and W{\"u}nnemann, Florian and Chetaille, Philippe and Prince, Andrea and Godard, Beatrice and Leclerc, Severine and Sobreira, Nara and Ling, Hua and Awadalla, Philip and Thibeault, Maryse and Khairy, Paul and Samuels, Mark E and Andelfinger, Gregor} } @article {47, title = {Family-Based Rare Variant Association Analysis: A Fast and Efficient Method of Multivariate Phenotype Association Analysis.}, journal = {Genet Epidemiol}, volume = {40}, year = {2016}, month = {2016 Sep}, pages = {502-11}, abstract = {

Family-based designs have been repeatedly shown to be powerful in detecting the significant rare variants associated with human diseases. Furthermore, human diseases are often defined by the outcomes of multiple phenotypes, and thus we expect multivariate family-based analyses may be very efficient in detecting associations with rare variants. However, few statistical methods implementing this strategy have been developed for family-based designs. In this report, we describe one such implementation: the multivariate family-based rare variant association tool (mFARVAT). mFARVAT is a quasi-likelihood-based score test for rare variant association analysis with multiple phenotypes, and tests both homogeneous and heterogeneous effects of each variant on multiple phenotypes. Simulation results show that the proposed method is generally robust and efficient for various disease models, and we identify some promising candidate genes associated with chronic obstructive pulmonary disease. The software of mFARVAT is freely available at http://healthstat.snu.ac.kr/software/mfarvat/, implemented in C++ and supported on Linux and MS Windows.

}, keywords = {Computer Simulation, Genetic Association Studies, Genetic Variation, Humans, Likelihood Functions, Models, Genetic, Phenotype}, issn = {1098-2272}, doi = {10.1002/gepi.21985}, author = {Wang, Longfei and Lee, Sungyoung and Gim, Jungsoo and Qiao, Dandi and Cho, Michael and Elston, Robert C and Silverman, Edwin K and Won, Sungho} } @article {86, title = {FOXE3 mutations predispose to thoracic aortic aneurysms and dissections.}, journal = {J Clin Invest}, volume = {126}, year = {2016}, month = {2016 Mar 01}, pages = {948-61}, abstract = {

The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3-/- mice with p53-/- mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.

}, keywords = {Adult, Aneurysm, Dissecting, Animals, Aorta, Aortic Aneurysm, Thoracic, Apoptosis, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p21, Female, Forkhead Transcription Factors, Gene Expression, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Muscle, Smooth, Vascular, Mutation, Missense, Myocytes, Smooth Muscle, Pedigree, Tumor Suppressor Protein p53, Vascular Remodeling, Zebrafish}, issn = {1558-8238}, doi = {10.1172/JCI83778}, author = {Kuang, Shao-Qing and Medina-Martinez, Olga and Guo, Dong-Chuan and Gong, Limin and Regalado, Ellen S and Reynolds, Corey L and Boileau, Catherine and Jondeau, Guillaume and Prakash, Siddharth K and Kwartler, Callie S and Zhu, Lawrence Yang and Peters, Andrew M and Duan, Xue-Yan and Bamshad, Michael J and Shendure, Jay and Nickerson, Debbie A and Santos-Cortez, Regie L and Dong, Xiurong and Leal, Suzanne M and Majesky, Mark W and Swindell, Eric C and Jamrich, Milan and Milewicz, Dianna M} } @article {105, title = {Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features.}, journal = {Genet Med}, volume = {18}, year = {2016}, month = {2016 08}, pages = {788-95}, abstract = {

PURPOSE: The pace of Mendelian gene discovery is slowed by the "n-of-1 problem"-the difficulty of establishing the causality of a putatively pathogenic variant in a single person or family. Identification of an unrelated person with an overlapping phenotype and suspected pathogenic variant in the same gene can overcome this barrier, but it is often impeded by lack of a convenient or widely available way to share data on candidate variants/genes among families, clinicians, and researchers.

METHODS: Social networking among families, clinicians, and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes.

RESULTS: De novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features.

CONCLUSION: Social networking is a potentially powerful strategy to discover genes for rare Mendelian conditions, particularly those with nonspecific phenotypic features. To facilitate the efforts of families to share phenotypic and genomic information with each other, clinicians, and researchers, we developed the Repository for Mendelian Genomics Family Portal (RMD-FP; http://uwcmg.org/$\#$/family). Design and development of MyGene2 (http://www.mygene2.org), a Web-based tool that enables families, clinicians, and researchers to search for gene matches based on analysis of phenotype and exome data deposited into the RMD-FP, is under way.Genet Med 18 8, 788-795.

}, keywords = {Child, Child, Preschool, Databases, Factual, Developmental Disabilities, Female, Genetic Association Studies, Histone Demethylases, Humans, Information Dissemination, Male, Mutation, Missense, Phenotype, Social Networking, Web Browser}, issn = {1530-0366}, doi = {10.1038/gim.2015.161}, author = {Chong, Jessica X and Yu, Joon-Ho and Lorentzen, Peter and Park, Karen M and Jamal, Seema M and Tabor, Holly K and Rauch, Anita and Saenz, Margarita Sifuentes and Boltshauser, Eugen and Patterson, Karynne E and Nickerson, Deborah A and Bamshad, Michael J} } @article {75, title = {Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Mar 03}, pages = {562-570}, abstract = {

The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.

}, keywords = {Adolescent, Alleles, Amino Acid Sequence, Atrophy, Cerebellum, Child, Child, Preschool, Developmental Disabilities, Endoplasmic Reticulum-Associated Degradation, Female, Genetic Association Studies, Genetic Variation, Heterozygote, Humans, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Muscle Hypotonia, Mutation, Pedigree, Protein Folding, Proteins, Scoliosis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.01.011}, author = {Harel, Tamar and Yesil, G{\"o}zde and Bayram, Yavuz and Coban-Akdemir, Zeynep and Charng, Wu-Lin and Karaca, Ender and Al Asmari, Ali and Eldomery, Mohammad K and Hunter, Jill V and Jhangiani, Shalini N and Rosenfeld, Jill A and Pehlivan, Davut and El-Hattab, Ayman W and Saleh, Mohammed A and LeDuc, Charles A and Muzny, Donna and Boerwinkle, Eric and Gibbs, Richard A and Chung, Wendy K and Yang, Yaping and Belmont, John W and Lupski, James R} } @article {55, title = {Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes.}, journal = {J Med Genet}, volume = {53}, year = {2016}, month = {2016 09}, pages = {608-15}, abstract = {

BACKGROUND: Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene.

METHODS: Exome sequencing was performed in 145 patients with Joubert syndrome (JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes.

RESULTS: We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy (JATD). The CEP120-associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype.

CONCLUSION: Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1\% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Cell Cycle Proteins, Cerebellar Diseases, Cerebellum, Child, Ciliopathies, Encephalocele, Eye Abnormalities, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Kidney Diseases, Cystic, Male, Mutation, Mutation Rate, Orofaciodigital Syndromes, Pedigree, Phenotype, Retina, Sequence Alignment}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-103832}, author = {Roosing, Susanne and Romani, Marta and Isrie, Mala and Rosti, Rasim Ozgur and Micalizzi, Alessia and Musaev, Damir and Mazza, Tommaso and Al-Gazali, Lihadh and Altunoglu, Umut and Boltshauser, Eugen and D{\textquoteright}Arrigo, Stefano and De Keersmaecker, Bart and Kayserili, H{\"u}lya and Brandenberger, Sarah and Kraoua, Ichraf and Mark, Paul R and McKanna, Trudy and Van Keirsbilck, Joachim and Moerman, Philippe and Poretti, Andrea and Puri, Ratna and Van Esch, Hilde and Gleeson, Joseph G and Valente, Enza Maria} } @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 {82, title = {Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports.}, journal = {Am J Med Genet A}, volume = {170A}, year = {2016}, month = {2016 May}, pages = {1165-73}, abstract = {

Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis.

}, keywords = {Autistic Disorder, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 16, Comparative Genomic Hybridization, Developmental Disabilities, DNA Copy Number Variations, Female, Genetic Association Studies, Humans, Male, Psychotic Disorders, Schizophrenia, Signal Transduction}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37595}, author = {Brownstein, Catherine A and Kleiman, Robin J and Engle, Elizabeth C and Towne, Meghan C and D{\textquoteright}Angelo, Eugene J and Yu, Timothy W and Beggs, Alan H and Picker, Jonathan and Fogler, Jason M and Carroll, Devon and Schmitt, Rachel C O and Wolff, Robert R and Shen, Yiping and Lip, Va and Bilguvar, Kaya and Kim, April and Tembulkar, Sahil and O{\textquoteright}Donnell, Kyle and Gonzalez-Heydrich, Joseph} } @article {96, title = {A patient with a novel homozygous missense mutation in FTO and concomitant nonsense mutation in CETP.}, journal = {J Hum Genet}, volume = {61}, year = {2016}, month = {2016 May}, pages = {395-403}, abstract = {

The fat mass and obesity associated (FTO) gene has previously been associated with a variety of diseases and conditions, notably obesity, acute coronary syndrome and metabolic syndrome. Reports describing mutations in FTO as well as in FTO animal models have further demonstrated a role for FTO in the development of the brain and other organs. Here, we describe a patient born of consanguineous union who presented with microcephaly, developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia and other various phenotypic abnormalities. Whole-exome sequencing revealed a novel homozygous missense mutation in FTO and a nonsense mutation in the cholesteryl ester transfer protein (CETP). Exome copy number variation analysis revealed no disease-causing large duplications or deletions within coding regions. Patient{\textquoteright}s, her parents{\textquoteright} and non-related control{\textquoteright} fibroblasts were analyzed for morphologic defects, abnormal proliferation, apoptosis and transcriptome profile. We have shown that FTO is located in the nucleus of cells from each tested sample. Western blot analysis demonstrated no changes in patient FTO. Quantitative (qPCR) analysis revealed slightly decreased levels of FTO expression in patient cells compared with controls. No morphological or proliferation differences between the patient and control fibroblasts were observed. There is still much to be learned about the molecular mechanisms by which mutations in FTO contribute to such severe phenotypes.

}, keywords = {Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Apoptosis, Biopsy, Child, Preschool, Cholesterol Ester Transfer Proteins, Computational Biology, Consanguinity, DNA Copy Number Variations, DNA Mutational Analysis, Exome, Female, Gene Expression, Gene Expression Profiling, Genetic Association Studies, Genotype, High-Throughput Nucleotide Sequencing, Homozygote, Humans, Mutation, Missense, Phenotype, Transcriptome}, issn = {1435-232X}, doi = {10.1038/jhg.2015.160}, author = {{\c C}a{\u g}layan, Ahmet O and Tuysuz, Beyhan and Co{\c s}kun, S{\"u}leyman and Quon, Jennifer and Harmanc{\i}, Akdes S and Baranoski, Jacob F and Baran, Bur{\c c}in and Erson-Omay, E Zeynep and Henegariu, Octavian and Mane, Shrikant M and Bilguvar, Kaya and Yasuno, Katsuhito and G{\"u}nel, Murat} } @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 {531, title = {Update on the Toriello-Carey syndrome.}, journal = {Am J Med Genet A}, volume = {170}, year = {2016}, month = {2016 10}, pages = {2551-8}, abstract = {

Toriello and Carey described a provisionally-unique syndrome comprised of agenesis of the corpus callosum, Pierre Robin anomaly, and a characteristic facial phenotype. Because the condition affected siblings, this entity was postulated to be an autosomal recessive multiple anomaly syndrome. Several patients were subsequently reported, and over time, it became apparent that the Toriello-Carey syndrome was etiologically heterogeneous. Based on previous reports, it is estimated that at least 20\% of patients with a clinical diagnosis of Toriello-Carey syndrome have a chromosomal anomaly as the basis of the phenotype. However, no basis for the non-chromosomal cases has been found. This review summarizes the literature to date and provides speculation regarding the possible explanations for failing to find the cause of Toriello-Carey syndrome. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Agenesis of Corpus Callosum, Chromosome Aberrations, Craniofacial Abnormalities, Female, Genetic Association Studies, Heart Defects, Congenital, Humans, Limb Deformities, Congenital, Male, Phenotype, Pierre Robin Syndrome, Urogenital Abnormalities}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37735}, author = {Toriello, Helga V and Colley, Chelsey and Bamshad, Michael} } @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 {147, title = {Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Nov}, pages = {1080-7}, abstract = {

The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80\% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.

}, keywords = {Adolescent, Adult, Alleles, Amino Acid Substitution, Child, DNA Mutational Analysis, Exome, Facies, Female, Genetic Association Studies, Genotype, Humans, Male, Models, Molecular, Mutation, Noonan Syndrome, Phenotype, Protein Conformation, Protein Interaction Domains and Motifs, Son of Sevenless Proteins, Young Adult}, issn = {1098-1004}, doi = {10.1002/humu.22834}, author = {Cordeddu, Viviana and Yin, Jiani C and Gunnarsson, Cecilia and Virtanen, Carl and Drunat, S{\'e}verine and Lepri, Francesca and De Luca, Alessandro and Rossi, Cesare and Ciolfi, Andrea and Pugh, Trevor J and Bruselles, Alessandro and Priest, James R and Pennacchio, Len A and Lu, Zhibin and Danesh, Arnavaz and Quevedo, Rene and Hamid, Alaa and Martinelli, Simone and Pantaleoni, Francesca and Gnazzo, Maria and Daniele, Paola and Lissewski, Christina and Bocchinfuso, Gianfranco and Stella, Lorenzo and Odent, Sylvie and Philip, Nicole and Faivre, Laurence and Vlckova, Marketa and Seemanova, Eva and Digilio, Cristina and Zenker, Martin and Zampino, Giuseppe and Verloes, Alain and Dallapiccola, Bruno and Roberts, Amy E and Cav{\'e}, H{\'e}l{\`e}ne and Gelb, Bruce D and Neel, Benjamin G and Tartaglia, Marco} } @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 {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 {180, title = {Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 May}, pages = {512-7}, abstract = {

Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial kindreds with pulmonary fibrosis. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no previous connection to telomere biology or disease, with five new heterozygous damaging mutations in unrelated cases and none in controls (P = 1.3 {\texttimes} 10(-8)); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more new damaging and missense variants at conserved residues in cases than in controls (P = 1.6 {\texttimes} 10(-6)). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members. Together, these genes explain ~7\% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.

}, keywords = {Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Case-Control Studies, Cells, Cultured, DNA Helicases, DNA Mutational Analysis, Exome, Exoribonucleases, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Idiopathic Pulmonary Fibrosis, Leukocytes, Lod Score, Male, Middle Aged, Molecular Sequence Data, Pedigree, Telomere, Telomere Shortening}, issn = {1546-1718}, doi = {10.1038/ng.3278}, author = {Stuart, Bridget D and Choi, Jungmin and Zaidi, Samir and Xing, Chao and Holohan, Brody and Chen, Rui and Choi, Mihwa and Dharwadkar, Pooja and Torres, Fernando and Girod, Carlos E and Weissler, Jonathan and Fitzgerald, John and Kershaw, Corey and Klesney-Tait, Julia and Mageto, Yolanda and Shay, Jerry W and Ji, Weizhen and Bilguvar, Kaya and Mane, Shrikant and Lifton, Richard P and Garcia, Christine Kim} } @article {188, title = {FBN1 contributing to familial congenital diaphragmatic hernia.}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Apr}, pages = {831-6}, abstract = {

Congenital diaphragmatic hernia (CDH) is a relatively common, life--threatening birth defect. We present a family with recurrent CDH--paraesophageal and central--for whom exome sequencing (ES) revealed a frameshift mutation (c.4969_4970insA, p.Ile1657Asnfs*30) in the fibrillin 1 gene (FBN1) that causes Marfan syndrome. A diagnosis of Marfan syndrome had not been considered previously in this family. However, a review of the literature demonstrated that FBN1 mutations have an unusual pattern of CDH in which paraesophageal hernias are particularly common. Subsequent clinical evaluations revealed evidence for ectopia lentis in affected family members supporting a clinical diagnosis of Marfan syndrome. Since only two other cases of familial CDH have been described in association with FBN1 mutations, we investigated an oligogenic hypothesis by examining ES data for deleterious sequence changes in other CDH-related genes. This search revealed putatively deleterious sequence changes in four other genes that have been shown to cause diaphragm defects in humans and/or mice--FREM1, DES, PAX3 and MET. It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. However, their individual contribution is likely to be small compared to that of the frameshift mutation in FBN1. We conclude that ES can be used to identify both major and minor genetic factors that may contribute to CDH. These results also suggest that ES should be considered in the diagnostic evaluation of individuals and families with CDH, particularly when other diagnostic modalities have failed to reveal a molecular etiology.

}, keywords = {Adult, Child, Preschool, DNA Mutational Analysis, Exome, Female, Fibrillin-1, Fibrillins, Frameshift Mutation, Genetic Association Studies, Hernias, Diaphragmatic, Congenital, Humans, Male, Marfan Syndrome, Microfilament Proteins, Pedigree}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36960}, author = {Beck, Tyler F and Campeau, Philippe M and Jhangiani, Shalini N and Gambin, Tomasz and Li, Alexander H and Abo-Zahrah, Reem and Jordan, Valerie K and Hernandez-Garcia, Andres and Wiszniewski, Wojciech K and Muzny, Donna and Gibbs, Richard A and Boerwinkle, Eric and Lupski, James R and Lee, Brendan and Reardon, Willie and Scott, Daryl A} } @article {121, title = {Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.}, journal = {Neuron}, volume = {88}, year = {2015}, month = {2015 Nov 04}, pages = {499-513}, abstract = {

Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85\% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.

}, keywords = {Brain, Cohort Studies, Databases, Genetic, Female, Gene Regulatory Networks, Genetic Association Studies, Genetic Variation, Humans, Male, Mendelian Randomization Analysis, Nervous System Diseases, Pedigree}, issn = {1097-4199}, doi = {10.1016/j.neuron.2015.09.048}, author = {Karaca, Ender and Harel, Tamar and Pehlivan, Davut and Jhangiani, Shalini N and Gambin, Tomasz and Coban Akdemir, Zeynep and Gonzaga-Jauregui, Claudia and Erdin, Serkan and Bayram, Yavuz and Campbell, Ian M and Hunter, Jill V and Atik, Mehmed M and Van Esch, Hilde and Yuan, Bo and Wiszniewski, Wojciech and Isikay, Sedat and Yesil, G{\"o}zde and Yuregir, Ozge O and Tug Bozdogan, Sevcan and Aslan, Huseyin and Aydin, Hatip and Tos, Tulay and Aksoy, Ayse and De Vivo, Darryl C and Jain, Preti and Geckinli, B Bilge and Sezer, Ozlem and Gul, Davut and Durmaz, Burak and Cogulu, Ozgur and Ozkinay, Ferda and Topcu, Vehap and Candan, Sukru and Cebi, Alper Han and Ikbal, Mevlit and Yilmaz Gulec, Elif and Gezdirici, Alper and Koparir, Erkan and Ekici, Fatma and Coskun, Salih and Cicek, Salih and Karaer, Kadri and Koparir, Asuman and Duz, Mehmet Bugrahan and Kirat, Emre and Fenercioglu, Elif and Ulucan, Hakan and Seven, Mehmet and Guran, Tulay and Elcioglu, Nursel and Yildirim, Mahmut Selman and Aktas, Dilek and Alika{\c s}ifo{\u g}lu, Mehmet and Ture, Mehmet and Yakut, Tahsin and Overton, John D and Yuksel, Adnan and Ozen, Mustafa and Muzny, Donna M and Adams, David R and Boerwinkle, Eric and Chung, Wendy K 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 {155, title = {Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.}, journal = {J Med Genet}, volume = {52}, year = {2015}, month = {2015 Aug}, pages = {514-22}, abstract = {

BACKGROUND: Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS.

METHODS: We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next-generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion algorithm with an optimised score cut-off.

RESULTS: We identified presumed causal variants in 62\% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34\% of individuals have a {\textquoteright}pure JS{\textquoteright} phenotype. Retinal disease is present in 30\% of individuals, renal disease in 25\%, coloboma in 17\%, polydactyly in 15\%, liver fibrosis in 14\% and encephalocele in 8\%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS subtypes.

CONCLUSIONS: This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes and enable gene-specific treatments in the future.

}, keywords = {Abnormalities, Multiple, Cerebellum, Cohort Studies, DNA Mutational Analysis, Eye Abnormalities, Genetic Association Studies, Genetic Heterogeneity, Humans, Kidney Diseases, Cystic, Models, Theoretical, Pedigree, Retina, Sequence Analysis, DNA}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2015-103087}, author = {Bachmann-Gagescu, R and Dempsey, J C and Phelps, I G and O{\textquoteright}Roak, B J and Knutzen, D M and Rue, T C and Ishak, G E and Isabella, C R and Gorden, N and Adkins, J and Boyle, E A and de Lacy, N and O{\textquoteright}Day, D and Alswaid, A and Ramadevi A, Radha and Lingappa, L and Louren{\c c}o, C and Martorell, L and Garcia-Cazorla, {\`A} and Ozy{\"u}rek, H and Halilo{\u g}lu, G and Tuysuz, B and Top{\c c}u, M and Chance, P and Parisi, M A and Glass, I A and Shendure, J and Doherty, D} } @article {154, title = {KIAA0586 is Mutated in Joubert Syndrome.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Sep}, pages = {831-5}, abstract = {

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. JS is part of a group of disorders called ciliopathies based on their overlapping phenotypes and common underlying pathophysiology linked to primary cilium dysfunction. Biallelic mutations in one of 28 genes, all encoding proteins localizing to the primary cilium or basal body, can cause JS. Despite this large number of genes, the genetic cause can currently be determined in about 62\% of individuals with JS. To identify novel JS genes, we performed whole exome sequencing on 35 individuals with JS and found biallelic rare deleterious variants (RDVs) in KIAA0586, encoding a centrosomal protein required for ciliogenesis, in one individual. Targeted next-generation sequencing in a large JS cohort identified biallelic RDVs in eight additional families for an estimated prevalence of 2.5\% (9/366 JS families). All affected individuals displayed JS phenotypes toward the mild end of the spectrum.

}, keywords = {Abnormalities, Multiple, Adolescent, Adult, Alternative Splicing, Brain, Cell Cycle Proteins, Cerebellum, Child, Child, Preschool, DNA Mutational Analysis, Eye Abnormalities, Gene Order, Genetic Association Studies, Humans, Kidney Diseases, Cystic, Magnetic Resonance Imaging, Mutation, Phenotype, Retina, Young Adult}, issn = {1098-1004}, doi = {10.1002/humu.22821}, author = {Bachmann-Gagescu, Ruxandra and Phelps, Ian G and Dempsey, Jennifer C and Sharma, Vivek A and Ishak, Gisele E and Boyle, Evan A and Wilson, Meredith and Marques Louren{\c c}o, Charles and Arslan, Mutluay and Shendure, Jay and Doherty, Dan} } @article {131, title = {The Matchmaker Exchange: a platform for rare disease gene discovery.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Oct}, pages = {915-21}, abstract = {

There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for "the needle in a haystack" to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease-specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can "match" these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow.

}, keywords = {Database Management Systems, Databases, Genetic, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Information Dissemination, Rare Diseases, Software}, issn = {1098-1004}, doi = {10.1002/humu.22858}, author = {Philippakis, Anthony A and Azzariti, Danielle R and Beltran, Sergi and Brookes, Anthony J and Brownstein, Catherine A and Brudno, Michael and Brunner, Han G and Buske, Orion J and Carey, Knox and Doll, Cassie and Dumitriu, Sergiu and Dyke, Stephanie O M and den Dunnen, Johan T and Firth, Helen V and Gibbs, Richard A and Girdea, Marta and Gonzalez, Michael and Haendel, Melissa A and Hamosh, Ada and Holm, Ingrid A and Huang, Lijia and Hurles, Matthew E and Hutton, Ben and Krier, Joel B and Misyura, Andriy and Mungall, Christopher J and Paschall, Justin and Paten, Benedict and Robinson, Peter N and Schiettecatte, Fran{\c c}ois and Sobreira, Nara L and Swaminathan, Ganesh J and Taschner, Peter E and Terry, Sharon F and Washington, Nicole L and Z{\"u}chner, Stephan and Boycott, Kym M and Rehm, Heidi L} } @article {193, title = {New tools for Mendelian disease gene identification: PhenoDB variant analysis module; and GeneMatcher, a web-based tool for linking investigators with an interest in the same gene.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Apr}, pages = {425-31}, abstract = {

Identifying the causative variant from among the thousands identified by whole-exome sequencing or whole-genome sequencing is a formidable challenge. To make this process as efficient and flexible as possible, we have developed a Variant Analysis Module coupled to our previously described Web-based phenotype intake tool, PhenoDB (http://researchphenodb.net and http://phenodb.org). When a small number of candidate-causative variants have been identified in a study of a particular patient or family, a second, more difficult challenge becomes proof of causality for any given variant. One approach to this problem is to find other cases with a similar phenotype and mutations in the same candidate gene. Alternatively, it may be possible to develop biological evidence for causality, an approach that is assisted by making connections to basic scientists studying the gene of interest, often in the setting of a model organism. Both of these strategies benefit from an open access, online site where individual clinicians and investigators could post genes of interest. To this end, we developed GeneMatcher (http://genematcher.org), a freely accessible Website that enables connections between clinicians and researchers across the world who share an interest in the same gene(s).

}, keywords = {Computational Biology, Databases, Genetic, Genetic Association Studies, Genetic Diseases, Inborn, Genetic Variation, Genomics, Internet, Phenotype, Software, Web Browser}, issn = {1098-1004}, doi = {10.1002/humu.22769}, author = {Sobreira, Nara and Schiettecatte, Fran{\c c}ois and Boehm, Corinne and Valle, David and Hamosh, Ada} } @article {176, title = {PacBio-LITS: a large-insert targeted sequencing method for characterization of human disease-associated chromosomal structural variations.}, journal = {BMC Genomics}, volume = {16}, year = {2015}, month = {2015 Mar 19}, pages = {214}, abstract = {

BACKGROUND: Generation of long (>5 Kb) DNA sequencing reads provides an approach for interrogation of complex regions in the human genome. Currently, large-insert whole genome sequencing (WGS) technologies from Pacific Biosciences (PacBio) enable analysis of chromosomal structural variations (SVs), but the cost to achieve the required sequence coverage across the entire human genome is high.

RESULTS: We developed a method (termed PacBio-LITS) that combines oligonucleotide-based DNA target-capture enrichment technologies with PacBio large-insert library preparation to facilitate SV studies at specific chromosomal regions. PacBio-LITS provides deep sequence coverage at the specified sites at substantially reduced cost compared with PacBio WGS. The efficacy of PacBio-LITS is illustrated by delineating the breakpoint junctions of low copy repeat (LCR)-associated complex structural rearrangements on chr17p11.2 in patients diagnosed with Potocki-Lupski syndrome (PTLS; MIM$\#$610883). We successfully identified previously determined breakpoint junctions in three PTLS cases, and also were able to discover novel junctions in repetitive sequences, including LCR-mediated breakpoints. The new information has enabled us to propose mechanisms for formation of these structural variants.

CONCLUSIONS: The new method leverages the cost efficiency of targeted capture-sequencing as well as the mappability and scaffolding capabilities of long sequencing reads generated by the PacBio platform. It is therefore suitable for studying complex SVs, especially those involving LCRs, inversions, and the generation of chimeric Alu elements at the breakpoints. Other genomic research applications, such as haplotype phasing and small insertion and deletion validation could also benefit from this technology.

}, keywords = {Chromosome Aberrations, Gene Library, Gene Rearrangement, Genetic Association Studies, Genomics, High-Throughput Nucleotide Sequencing, Humans, Workflow}, issn = {1471-2164}, doi = {10.1186/s12864-015-1370-2}, author = {Wang, Min and Beck, Christine R and English, Adam C and Meng, Qingchang and Buhay, Christian and Han, Yi and Doddapaneni, Harsha V and Yu, Fuli and Boerwinkle, Eric and Lupski, James R and Muzny, Donna M and Gibbs, Richard A} } @article {268, title = {Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.}, journal = {Science}, volume = {343}, year = {2014}, month = {2014 Jan 31}, pages = {506-511}, abstract = {

Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

}, keywords = {Animals, Axons, Biological Transport, Cohort Studies, Exome, Gene Regulatory Networks, Genetic Association Studies, Humans, Motor Neuron Disease, Mutation, Neurons, Nucleotides, Pyramidal Tracts, Sequence Analysis, DNA, Spastic Paraplegia, Hereditary, Synapses, Transcriptome, Zebrafish}, issn = {1095-9203}, doi = {10.1126/science.1247363}, author = {Novarino, Gaia and Fenstermaker, Ali G and Zaki, Maha S and Hofree, Matan and Silhavy, Jennifer L and Heiberg, Andrew D and Abdellateef, Mostafa and Rosti, Basak and Scott, Eric and Mansour, Lobna and Masri, Amira and Kayserili, H{\"u}lya and Al-Aama, Jumana Y and Abdel-Salam, Ghada M H and Karminejad, Ariana and Kara, Majdi and Kara, Bulent and Bozorgmehri, Bita and Ben-Omran, Tawfeg and Mojahedi, Faezeh and El Din Mahmoud, Iman Gamal and Bouslam, Naima and Bouhouche, Ahmed and Benomar, Ali and Hanein, Sylvain and Raymond, Laure and Forlani, Sylvie and Mascaro, Massimo and Selim, Laila and Shehata, Nabil and Al-Allawi, Nasir and Bindu, P S and Azam, Matloob and G{\"u}nel, Murat and Caglayan, Ahmet and Bilguvar, Kaya and Tolun, Aslihan and Issa, Mahmoud Y and Schroth, Jana and Spencer, Emily G and Rosti, Rasim O and Akizu, Naiara and Vaux, Keith K and Johansen, Anide and Koh, Alice A and Megahed, Hisham and Durr, Alexandra and Brice, Alexis and Stevanin, Giovanni and Gabriel, Stacy B and Ideker, Trey and Gleeson, Joseph G} } @article {263, title = {Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype.}, journal = {Am J Respir Crit Care Med}, volume = {189}, year = {2014}, month = {2014 Mar 15}, pages = {707-17}, abstract = {

RATIONALE: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD.

OBJECTIVES: To identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD.

METHODS: Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing. Sanger-based sequencing was used for mutation scanning, validation, and segregation analysis.

MEASUREMENTS AND MAIN RESULTS: We performed exome sequencing on an affected sib-pair with normal ultrastructure in more than 85\% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in nine additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in patients with PCD with other gene mutations (98.3 vs. 20.7 nl/min; P < 0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared with 75 age- and sex-matched PCD cases (73.0 vs. 61.8, FEV1 \% predicted; P = 0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.1 {\textpm} Hz at 25{\textdegree}C), but an abnormal, circular beat pattern.

CONCLUSIONS: The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function.

}, keywords = {Adolescent, Adult, Child, Cilia, DNA Mutational Analysis, DNA-Binding Proteins, Exome, Female, Genetic Association Studies, Genetic Markers, Genetic Testing, Homozygote, Humans, Kartagener Syndrome, Linear Models, Male, Middle Aged, Mutation, Nasal Mucosa, Sequence Analysis, DNA, Young Adult}, issn = {1535-4970}, doi = {10.1164/rccm.201311-2047OC}, author = {Knowles, Michael R and Ostrowski, Lawrence E and Leigh, Margaret W and Sears, Patrick R and Davis, Stephanie D and Wolf, Whitney E and Hazucha, Milan J and Carson, Johnny L and Olivier, Kenneth N and Sagel, Scott D and Rosenfeld, Margaret and Ferkol, Thomas W and Dell, Sharon D and Milla, Carlos E and Randell, Scott H and Yin, Weining and Sannuti, Aruna and Metjian, Hilda M and Noone, Peadar G and Noone, Peter J and Olson, Christina A and Patrone, Michael V and Dang, Hong and Lee, Hye-Seung and Hurd, Toby W and Gee, Heon Yung and Otto, Edgar A and Halbritter, Jan and Kohl, Stefan and Kircher, Martin and Krischer, Jeffrey and Bamshad, Michael J and Nickerson, Deborah A and Hildebrandt, Friedhelm and Shendure, Jay and Zariwala, Maimoona A} } @article {250, title = {Power analysis and sample size estimation for sequence-based association studies.}, journal = {Bioinformatics}, volume = {30}, year = {2014}, month = {2014 Aug 15}, pages = {2377-8}, abstract = {

MOTIVATION: Statistical methods have been developed to test for complex trait rare variant (RV) associations, in which variants are aggregated across a region, which is typically a gene. Power analysis and sample size estimation for sequence-based RV association studies are challenging because of the necessity to realistically model the underlying allelic architecture of complex diseases within a suitable analytical framework to assess the performance of a variety of RV association methods in an unbiased manner.

SUMMARY: We developed SEQPower, a software package to perform statistical power analysis for sequence-based association data under a variety of genetic variant and disease phenotype models. It aids epidemiologists in determining the best study design, sample size and statistical tests for sequence-based association studies. It also provides biostatisticians with a platform to fairly compare RV association methods and to validate and assess novel association tests.

AVAILABILITY AND IMPLEMENTATION: The SEQPower program, source code, multi-platform executables, documentation, list of association tests, examples and tutorials are available at http://bioinformatics.org/spower.

}, keywords = {Alleles, Data Interpretation, Statistical, Disease, Genetic Association Studies, Genetic Variation, Humans, Phenotype, Sample Size, Sequence Analysis, DNA, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btu296}, author = {Wang, Gao T and Li, Biao and Santos-Cortez, Regie P Lyn and Peng, Bo and Leal, Suzanne M} } @article {279, title = {Rare-variant extensions of the transmission disequilibrium test: application to autism exome sequence data.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jan 02}, pages = {33-46}, abstract = {

Many population-based rare-variant (RV) association tests, which aggregate variants across a region, have been developed to analyze sequence data. A drawback of analyzing population-based data is that it is difficult to adequately control for population substructure and admixture, and spurious associations can occur. For RVs, this problem can be substantial, because the spectrum of rare variation can differ greatly between populations. A solution is to analyze parent-child trio data, by using the transmission disequilibrium test (TDT), which is robust to population substructure and admixture. We extended the TDT to test for RV associations using four commonly used methods. We demonstrate that for all RV-TDT methods, using proper analysis strategies, type I error is well-controlled even when there are high levels of population substructure or admixture. For trio data, unlike for population-based data, RV allele-counting association methods will lead to inflated type I errors. However type I errors can be properly controlled by obtaining p values empirically through haplotype permutation. The power of the RV-TDT methods was evaluated and compared to the analysis of case-control data with a number of genetic and disease models. The RV-TDT was also used to analyze exome data from 199 Simons Simplex Collection autism trios and an association was observed with variants in ABCA7. Given the problem of adequately controlling for population substructure and admixture in RV association studies and the growing number of sequence-based trio studies, the RV-TDT is extremely beneficial to elucidate the involvement of RVs in the etiology of complex traits.

}, keywords = {Alleles, Autistic Disorder, Computer Simulation, Exome, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Haplotypes, Humans, Linkage Disequilibrium, Models, Genetic, Phenotype, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.11.021}, author = {He, Zongxiao and O{\textquoteright}Roak, Brian J and Smith, Joshua D and Wang, Gao and Hooker, Stanley and Santos-Cortez, Regie Lyn P and Li, Biao and Kan, Mengyuan and Krumm, Nik and Nickerson, Deborah A and Shendure, Jay and Eichler, Evan E and Leal, Suzanne M} } @article {249, title = {Variant association tools for quality control and analysis of large-scale sequence and genotyping array data.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 May 01}, pages = {770-83}, abstract = {

Currently there is great interest in detecting associations between complex traits and rare variants. In this report, we describe Variant Association Tools (VAT) and the VAT pipeline, which implements best practices for rare-variant association studies. Highlights of VAT include variant-site and call-level quality control (QC), summary statistics, phenotype- and genotype-based sample selection, variant annotation, selection of variants for association analysis, and a collection of rare-variant association methods for analyzing qualitative and quantitative traits. The association testing framework for VAT is regression based, which readily allows for flexible construction of association models with multiple covariates and weighting themes based on allele frequencies or predicted functionality. Additionally, pathway analyses, conditional analyses, and analyses of gene-gene and gene-environment interactions can be performed. VAT is capable of rapidly scanning through data by using multi-process computation, adaptive permutation, and simultaneously conducting association analysis via multiple methods. Results are available in text or graphic file formats and additionally can be output to relational databases for further annotation and filtering. An interface to R language also facilitates user implementation of novel association methods. The VAT{\textquoteright}s data QC and association-analysis pipeline can be applied to sequence, imputed, and genotyping array, e.g., "exome chip," data, providing a reliable and reproducible computational environment in which to analyze small- to large-scale studies with data from the latest genotyping and sequencing technologies. Application of the VAT pipeline is demonstrated through analysis of data from the 1000 Genomes project.

}, keywords = {Genetic Association Studies, Genetic Variation, Genotyping Techniques, High-Throughput Nucleotide Sequencing, Humans, Multifactorial Inheritance, Quality Control, Software}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.04.004}, author = {Wang, Gao T and Peng, Bo and Leal, Suzanne M} } @article {300, title = {A recurrent PDGFRB mutation causes familial infantile myofibromatosis.}, journal = {Am J Hum Genet}, volume = {92}, year = {2013}, month = {2013 Jun 06}, pages = {996-1000}, abstract = {

Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor β (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-β promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-β as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-β in aggressive life-threatening familial forms of the disease.

}, keywords = {Amino Acid Sequence, Female, Genes, Dominant, Genetic Association Studies, Germ-Line Mutation, Heterozygote, Humans, Male, Models, Molecular, Mutation, Missense, Myofibromatosis, Pedigree, Protein Structure, Tertiary, Receptor, Notch3, Receptor, Platelet-Derived Growth Factor beta, Receptors, Notch, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.04.026}, author = {Cheung, Yee Him and Gayden, Tenzin and Campeau, Philippe M and LeDuc, Charles A and Russo, Donna and Nguyen, Van-Hung and Guo, Jiancheng and Qi, Ming and Guan, Yanfang and Albrecht, Steffen and Moroz, Brenda and Eldin, Karen W and Lu, James T and Schwartzentruber, Jeremy and Malkin, David and Berghuis, Albert M and Emil, Sherif and Gibbs, Richard A and Burk, David L and Vanstone, Megan and Lee, Brendan H and Orchard, David and Boycott, Kym M and Chung, Wendy K and Jabado, Nada} } @article {643, title = {A fast and noise-resilient approach to detect rare-variant associations with deep sequencing data for complex disorders.}, journal = {Genet Epidemiol}, volume = {36}, year = {2012}, month = {2012 Nov}, pages = {675-85}, abstract = {

Next generation sequencing technology has enabled the paradigm shift in genetic association studies from the common disease/common variant to common disease/rare-variant hypothesis. Analyzing individual rare variants is known to be underpowered; therefore association methods have been developed that aggregate variants across a genetic region, which for exome sequencing is usually a gene. The foreseeable widespread use of whole genome sequencing poses new challenges in statistical analysis. It calls for new rare-variant association methods that are statistically powerful, robust against high levels of noise due to inclusion of noncausal variants, and yet computationally efficient. We propose a simple and powerful statistic that combines the disease-associated P-values of individual variants using a weight that is the inverse of the expected standard deviation of the allele frequencies under the null. This approach, dubbed as Sigma-P method, is extremely robust to the inclusion of a high proportion of noncausal variants and is also powerful when both detrimental and protective variants are present within a genetic region. The performance of the Sigma-P method was tested using simulated data based on realistic population demographic and disease models and its power was compared to several previously published methods. The results demonstrate that this method generally outperforms other rare-variant association methods over a wide range of models. Additionally, sequence data on the ANGPTL family of genes from the Dallas Heart Study were tested for associations with nine metabolic traits and both known and novel putative associations were uncovered using the Sigma-P method.

}, keywords = {Angiopoietin-like 4 Protein, Angiopoietin-like Proteins, Angiopoietins, Case-Control Studies, Data Interpretation, Statistical, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Metabolism, Sequence Analysis, DNA, Texas, Triglycerides}, issn = {1098-2272}, doi = {10.1002/gepi.21662}, author = {Cheung, Yee Him and Wang, Gao and Leal, Suzanne M and Wang, Shuang} } @article {326, title = {SEQCHIP: a powerful method to integrate sequence and genotype data for the detection of rare variant associations.}, journal = {Bioinformatics}, volume = {28}, year = {2012}, month = {2012 Jul 01}, pages = {1745-51}, abstract = {

MOTIVATION: Next-generation sequencing greatly increases the capacity to detect rare-variant complex-trait associations. However, it is still expensive to sequence a large number of samples and therefore often small datasets are used. Given cost constraints, a potentially more powerful two-step strategy is to sequence a subset of the sample to discover variants, and genotype the identified variants in the remaining sample. If only cases are sequenced, directly combining sequence and genotype data will lead to inflated type-I errors in rare-variant association analysis. Although several methods have been developed to correct for the bias, they are either underpowered or theoretically invalid. We proposed a new method SEQCHIP to integrate genotype and sequence data, which can be used with most existing rare-variant tests.

RESULTS: It is demonstrated using both simulated and real datasets that the SEQCHIP method has controlled type-I errors, and is substantially more powerful than all other currently available methods.

AVAILABILITY: SEQCHIP is implemented in an R-Package and is available at http://linkage.rockefeller.edu/suzanne/seqchip/Seqchip.html.

}, keywords = {Adenoma, Case-Control Studies, Colorectal Neoplasms, Genetic Association Studies, Genetic Variation, Genotype, Humans, Phenotype, Sequence Analysis, DNA, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/bts263}, author = {Liu, Dajiang J and Leal, Suzanne M} } @article {321, title = {SimRare: a program to generate and analyze sequence-based data for association studies of quantitative and qualitative traits.}, journal = {Bioinformatics}, volume = {28}, year = {2012}, month = {2012 Oct 15}, pages = {2703-4}, abstract = {

MOTIVATION: Currently, there is great interest in detecting complex trait rare variant associations using next-generation sequence data. On a monthly basis, new rare variant association methods are published. It is difficult to evaluate these methods because there is no standard to generate data and often comparisons are biased. In order to fairly compare rare variant association methods, it is necessary to generate data using realistic population demographic and phenotypic models.

RESULT: SimRare is an interactive program that integrates generation of rare variant genotype/phenotype data and evaluation of association methods using a unified platform. Variant data are generated for gene regions using forward-time simulation that incorporates realistic population demographic and evolutionary scenarios. Phenotype data can be obtained for both case-control and quantitative traits. SimRare has a user-friendly interface that allows for easy entry of genetic and phenotypic parameters. Novel rare variant association methods implemented in R can also be imported into SimRare, to evaluate their performance and compare results, e.g. power and Type I error, with other currently available methods both numerically and graphically.

}, keywords = {Genetic Association Studies, Genetic Variation, Humans, Phenotype, Quantitative Trait, Heritable, Software}, issn = {1367-4811}, doi = {10.1093/bioinformatics/bts499}, author = {Li, Biao and Wang, Gao and Leal, Suzanne M} }