@article {994, title = {Identification of homozygous mutations for hearing loss.}, journal = {Gene}, volume = {778}, year = {2021}, month = {2021 Apr 30}, pages = {145464}, abstract = {

BACKGROUND: Hearing loss is the most common sensory disorder worldwide, affecting about 1 out of every 1000 newborns. The disease has major genetic components, and can be inherited as a single gene disorder either in autosomal dominant or recessive fashions. Due to the high rate of consanguineous unions, Iran has one of the highest prevalence of autosomal recessive nonsyndromic deafness (ARNSD) in the world.

METHODS: We carried out a genetic screening of ten Iranian kindreds with more than one offspring affected by ARNSD caused by consanguineous unions. Sanger sequencing and whole exome sequencing together with in silico 3D structure modeling and protein stability prediction were used to identify the underlying disease causing genes.

CONCLUSION: We identified the causes of deafness in all 10 kindred. In six kindreds homozygous mutations were identified in GJB2 gene by Sanger sequencing. By using whole exome sequencing (WES), a homozygous missense mutation was identified in ESRRB gene as the first ever reported disease gene in Iran. Also two novel homozygous frameshift and missense mutations were identified in MYO15A gene and one previously reported mutation in TMC1 gene in three independent kindred. Our study shows the efficacy of WES for unraveling new pathogenic mutations in ARNSD patients and expands the spectrum of genes contributing to ARNSD in the Iranian population. The findings of our study can facilitate future genetic screening of patients with ARNSD , early screening and optimal design of novel therapeutics.

}, keywords = {Connexin 26, Consanguinity, Female, Frameshift Mutation, Genetic Predisposition to Disease, Hearing Loss, Homozygote, Humans, Iran, Male, Membrane Proteins, Models, Molecular, Mutation, Missense, Myosins, Pedigree, Protein Stability, Receptors, Estrogen, Whole Exome Sequencing}, issn = {1879-0038}, doi = {10.1016/j.gene.2021.145464}, author = {Dianatpour, Mehdi and Smith, Emily and Hashemi, Seyed Basir and Farazifard, Mohammad A and Nezafat, Navid and Razban, Vahid and Mani, Arya} } @article {962, title = {Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling.}, journal = {Am J Hum Genet}, volume = {106}, year = {2020}, month = {2020 06 04}, pages = {779-792}, abstract = {

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

}, keywords = {Alleles, Base Sequence, Child, Child, Preschool, Cilia, Developmental Disabilities, Female, Hedgehog Proteins, Humans, Infant, Male, Models, Molecular, Neoplasms, Nerve Tissue Proteins, Nuclear Proteins, Pedigree, Signal Transduction, Smoothened Receptor, Zinc Finger Protein Gli2, Zinc Finger Protein Gli3}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.04.010}, author = {Le, Thuy-Linh and Sribudiani, Yunia and Dong, Xiaomin and Huber, Celine and Kois, Chelsea and Baujat, Genevi{\`e}ve and Gordon, Christopher T and Mayne, Valerie and Galmiche, Louise and Serre, Val{\'e}rie and Goudin, Nicolas and Zarhrate, Mohammed and Bole-Feysot, Christine and Masson, Cecile and Nitschk{\'e}, Patrick and Verheijen, Frans W and Pais, Lynn and Pelet, Anna and Sadedin, Simon and Pugh, John A and Shur, Natasha and White, Susan M and El Chehadeh, Salima and Christodoulou, John and Cormier-Daire, Val{\'e}rie and Hofstra, R M W and Lyonnet, Stanislas and Tan, Tiong Yang and Atti{\'e}-Bitach, Tania and Kerstjens-Frederikse, Wilhelmina S and Amiel, Jeanne and Thomas, Sophie} } @article {749, title = {A missense mutation in the catalytic domain of O-GlcNAc transferase links perturbations in protein O-GlcNAcylation to X-linked intellectual disability.}, journal = {FEBS Lett}, volume = {594}, year = {2020}, month = {2020 02}, pages = {717-727}, abstract = {

X-linked intellectual disabilities (XLID) are common developmental disorders. The enzyme O-GlcNAc transferase encoded by OGT, a recently discovered XLID gene, attaches O-GlcNAc to nuclear and cytoplasmic proteins. As few missense mutations have been described, it is unclear what the aetiology of the patient phenotypes is. Here, we report the discovery of a missense mutation in the catalytic domain of OGT in an XLID patient. X-ray crystallography reveals that this variant leads to structural rearrangements in the catalytic domain. The mutation reduces in~vitro OGT activity on substrate peptides/protein. Mouse embryonic stem cells carrying the mutation reveal reduced O-GlcNAcase (OGA) and global O-GlcNAc levels. These data suggest a direct link between changes in the O-GlcNAcome and intellectual disability observed in patients carrying OGT mutations.

}, keywords = {Animals, Catalytic Domain, Cell Line, Glycosylation, Humans, Intellectual Disability, Mice, Models, Molecular, Mutation, Missense, N-Acetylglucosaminyltransferases}, issn = {1873-3468}, doi = {10.1002/1873-3468.13640}, author = {Pravata, Veronica M and Gundogdu, Mehmet and Bartual, Sergio G and Ferenbach, Andrew T and Stavridis, Marios and {\~O}unap, Katrin and Pajusalu, Sander and {\v Z}ordania, Riina and Wojcik, Monica H and van Aalten, Daan M F} } @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 {574, title = {Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 02 12}, pages = {707}, abstract = {

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.

}, keywords = {Alleles, Anticodon, Child, Child, Preschool, Disease Progression, Epilepsy, Female, Genetic Predisposition to Disease, Humans, Longitudinal Studies, Loss of Function Mutation, Male, Microcephaly, Models, Molecular, Mutation, Neurodevelopmental Disorders, Pedigree, Protein Biosynthesis, Protein Interaction Domains and Motifs, RNA, Transfer, Valine-tRNA Ligase, Whole Exome Sequencing, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-018-07067-3}, author = {Friedman, Jennifer and Smith, Desiree E and Issa, Mahmoud Y and Stanley, Valentina and Wang, Rengang and Mendes, Marisa I and Wright, Meredith S and Wigby, Kristen and Hildreth, Amber and Crawford, John R and Koehler, Alanna E and Chowdhury, Shimul and Nahas, Shareef and Zhai, Liting and Xu, Zhiwen and Lo, Wing-Sze and James, Kiely N and Musaev, Damir and Accogli, Andrea and Guerrero, Kether and Tran, Luan T and Omar, Tarek E I and Ben-Omran, Tawfeg and Dimmock, David and Kingsmore, Stephen F and Salomons, Gajja S and Zaki, Maha S and Bernard, Genevi{\`e}ve and Gleeson, Joseph G} } @article {573, title = {Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 02 12}, pages = {708}, abstract = {

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.

}, keywords = {Alleles, Animals, Brain Diseases, Cell Line, Disease Models, Animal, Epilepsy, Female, Fibroblasts, Gene Knockout Techniques, Genetic Predisposition to Disease, Humans, Loss of Function Mutation, Male, Microcephaly, Models, Molecular, Neurodevelopmental Disorders, Pedigree, Prosencephalon, Valine-tRNA Ligase, Zebrafish}, issn = {2041-1723}, doi = {10.1038/s41467-018-07953-w}, author = {Siekierska, Aleksandra and Stamberger, Hannah and Deconinck, Tine and Oprescu, Stephanie N and Partoens, Mich{\`e}le and Zhang, Yifan and Sourbron, Jo and Adriaenssens, Elias and Mullen, Patrick and Wiencek, Patrick and Hardies, Katia and Lee, Jeong-Soo and Giong, Hoi-Khoanh and Distelmaier, Felix and Elpeleg, Orly and Helbig, Katherine L and Hersh, Joseph and Isikay, Sedat and Jordan, Elizabeth and Karaca, Ender and Kecskes, Angela and Lupski, James R and Kovacs-Nagy, Reka and May, Patrick and Narayanan, Vinodh and Pendziwiat, Manuela and Ramsey, Keri and Rangasamy, Sampathkumar and Shinde, Deepali N and Spiegel, Ronen and Timmerman, Vincent and von Spiczak, Sarah and Helbig, Ingo and Weckhuysen, Sarah and Francklyn, Christopher and Antonellis, Anthony and de Witte, Peter and De Jonghe, Peter} } @article {545, title = {A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0191224}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause (40-50\%) of chronic kidney disease (CKD) in children. About 40 monogenic causes of CAKUT have so far been discovered. To date less than 20\% of CAKUT cases can be explained by mutations in these 40 genes. To identify additional monogenic causes of CAKUT, we performed whole exome sequencing (WES) and homozygosity mapping (HM) in a patient with CAKUT from Indian origin and consanguineous descent. We identified a homozygous missense mutation (c.1336C>T, p.Arg446Cys) in the gene Von Willebrand factor A domain containing 2 (VWA2). With immunohistochemistry studies on kidneys of newborn (P1) mice, we show that Vwa2 and Fraser extracellular matrix complex subunit 1 (Fras1) co-localize in the nephrogenic zone of the renal cortex. We identified a pronounced expression of Vwa2 in the basement membrane of the ureteric bud (UB) and derivatives of the metanephric mesenchyme (MM). By applying in vitro assays, we demonstrate that the Arg446Cys mutation decreases translocation of monomeric VWA2 protein and increases translocation of aggregated VWA2 protein into the extracellular space. This is potentially due to the additional, unpaired cysteine residue in the mutated protein that is used for intermolecular disulfide bond formation. VWA2 is a known, direct interactor of FRAS1 of the Fraser-Complex (FC). FC-encoding genes and interacting proteins have previously been implicated in the pathogenesis of syndromic and/or isolated CAKUT phenotypes in humans. VWA2 therefore constitutes a very strong candidate in the search for novel CAKUT-causing genes. Our results from in vitro experiments indicate a dose-dependent neomorphic effect of the Arg446Cys homozygous mutation in VWA2.

}, keywords = {Amino Acid Sequence, Amino Acid Substitution, Animals, Animals, Newborn, Biomarkers, Tumor, Child, Consanguinity, Conserved Sequence, Exons, Extracellular Matrix Proteins, Fraser Syndrome, Gene Expression Regulation, Developmental, Homozygote, Humans, Male, Mice, Models, Animal, Models, Molecular, Mutation, Missense, Pedigree, Sequence Homology, Amino Acid, Urogenital Abnormalities, Urogenital System, Vesico-Ureteral Reflux}, issn = {1932-6203}, doi = {10.1371/journal.pone.0191224}, author = {van der Ven, Amelie T and Kobbe, Birgit and Kohl, Stefan and Shril, Shirlee and Pogoda, Hans-Martin and Imhof, Thomas and Ityel, Hadas and Vivante, Asaf and Chen, Jing and Hwang, Daw-Yang and Connaughton, Dervla M and Mann, Nina and Widmeier, Eugen and Taglienti, Mary and Schmidt, Johanna Magdalena and Nakayama, Makiko and Senguttuvan, Prabha and Kumar, Selvin and Tasic, Velibor and Kehinde, Elijah O and Mane, Shrikant M and Lifton, Richard P and Soliman, Neveen and Lu, Weining and Bauer, Stuart B and Hammerschmidt, Matthias and Wagener, Raimund and Hildebrandt, Friedhelm} } @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 {338, title = {Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jan 05}, pages = {117-127}, abstract = {

From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in~situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in \~{}0.1\% of individuals with unexplained neurodevelopmental disorders.

}, keywords = {Adolescent, Adult, Amino Acid Substitution, Ataxia, Child, Child, Preschool, Chromatin, Cyclin-Dependent Kinase Inhibitor p21, Developmental Disabilities, Exome, Face, Female, Gene Expression Regulation, Genes, Reporter, HEK293 Cells, Humans, Intellectual Disability, Language Development Disorders, Male, Models, Molecular, Mosaicism, Mutation, Neurodevelopmental Disorders, Protein Transport, Syndrome, Transcription Factors, Transcription, Genetic}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.11.012}, author = {Harms, Frederike Leonie and Girisha, Katta M and Hardigan, Andrew A and Kort{\"u}m, Fanny and Shukla, Anju and Alawi, Malik and Dalal, Ashwin and Brady, Lauren and Tarnopolsky, Mark and Bird, Lynne M and Ceulemans, Sophia and Bebin, Martina and Bowling, Kevin M and Hiatt, Susan M and Lose, Edward J and Primiano, Michelle and Chung, Wendy K and Juusola, Jane and Akdemir, Zeynep C and Bainbridge, Matthew and Charng, Wu-Lin and Drummond-Borg, Margaret and Eldomery, Mohammad K and El-Hattab, Ayman W and Saleh, Mohammed A M and B{\'e}zieau, St{\'e}phane and Cogn{\'e}, Benjamin and Isidor, Bertrand and K{\"u}ry, S{\'e}bastien and Lupski, James R and Myers, Richard M and Cooper, Gregory M and Kutsche, Kerstin} } @article {634, title = {Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Oct}, pages = {1529-1538}, abstract = {

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

}, keywords = {Animals, Apoptosis, Carrier Proteins, Cell Movement, CRISPR-Cas Systems, Cytoskeleton, DNA Repair, Endoplasmic Reticulum Stress, Gene Knockout Techniques, Hernia, Hiatal, Humans, Intracellular Signaling Peptides and Proteins, Metalloendopeptidases, Mice, Microcephaly, Models, Molecular, Multiprotein Complexes, Mutation, Nephrosis, Nephrotic Syndrome, Podocytes, Protein Conformation, Protein-Serine-Threonine Kinases, RNA Processing, Post-Transcriptional, RNA, Transfer, Telomere Homeostasis, Zebrafish, Zebrafish Proteins}, issn = {1546-1718}, doi = {10.1038/ng.3933}, author = {Braun, Daniela A and Rao, Jia and Mollet, Geraldine and Schapiro, David and Daugeron, Marie-Claire and Tan, Weizhen and Gribouval, Olivier and Boyer, Olivia and Revy, Patrick and Jobst-Schwan, Tilman and Schmidt, Johanna Magdalena and Lawson, Jennifer A and Schanze, Denny and Ashraf, Shazia and Ullmann, Jeremy F P and Hoogstraten, Charlotte A and Boddaert, Nathalie and Collinet, Bruno and Martin, Ga{\"e}lle and Liger, Dominique and Lovric, Svjetlana and Furlano, Monica and Guerrera, I Chiara and Sanchez-Ferras, Oraly and Hu, Jennifer F and Boschat, Anne-Claire and Sanquer, Sylvia and Menten, Bj{\"o}rn and Vergult, Sarah and De Rocker, Nina and Airik, Merlin and Hermle, Tobias and Shril, Shirlee and Widmeier, Eugen and Gee, Heon Yung and Choi, Won-Il and Sadowski, Carolin E and Pabst, Werner L and Warejko, Jillian K and Daga, Ankana and Basta, Tamara and Matejas, Verena and Scharmann, Karin and Kienast, Sandra D and Behnam, Babak and Beeson, Brendan and Begtrup, Amber and Bruce, Malcolm and Ch{\textquoteright}ng, Gaik-Siew and Lin, Shuan-Pei and Chang, Jui-Hsing and Chen, Chao-Huei and Cho, Megan T and Gaffney, Patrick M and Gipson, Patrick E and Hsu, Chyong-Hsin and Kari, Jameela A and Ke, Yu-Yuan and Kiraly-Borri, Cathy and Lai, Wai-Ming and Lemyre, Emmanuelle and Littlejohn, Rebecca Okashah and Masri, Amira and Moghtaderi, Mastaneh and Nakamura, Kazuyuki and Ozaltin, Fatih and Praet, Marleen and Prasad, Chitra and Prytula, Agnieszka and Roeder, Elizabeth R and Rump, Patrick and Schnur, Rhonda E and Shiihara, Takashi and Sinha, Manish D and Soliman, Neveen A and Soulami, Kenza and Sweetser, David A and Tsai, Wen-Hui and Tsai, Jeng-Daw and Topaloglu, Rezan and Vester, Udo and Viskochil, David H and Vatanavicharn, Nithiwat and Waxler, Jessica L and Wierenga, Klaas J and Wolf, Matthias T F and Wong, Sik-Nin and Leidel, Sebastian A and Truglio, Gessica and Dedon, Peter C and Poduri, Annapurna and Mane, Shrikant and Lifton, Richard P and Bouchard, Maxime and Kannu, Peter and Chitayat, David and Magen, Daniella and Callewaert, Bert and van Tilbeurgh, Herman and Zenker, Martin and Antignac, Corinne and Hildebrandt, Friedhelm} } @article {89, title = {Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Feb 04}, pages = {331-8}, abstract = {

The sphingosine-1-phosphate receptors (S1PRs) are a well-studied class of transmembrane G protein-coupled sphingolipid receptors that mediate multiple cellular processes. However, S1PRs have not been previously reported to be involved in the genetic etiology of human traits. S1PR2 lies within the autosomal-recessive nonsyndromic hearing impairment (ARNSHI) locus DFNB68 on 19p13.2. From exome sequence data we identified two pathogenic S1PR2 variants, c.323G>C (p.Arg108Pro) and c.419A>G (p.Tyr140Cys). Each of these variants co-segregates with congenital profound hearing impairment in consanguineous Pakistani families with maximum LOD scores of 6.4 for family DEM4154 and 3.3 for family PKDF1400. Neither S1PR2 missense variant was reported among \~{}120,000 chromosomes in the Exome Aggregation Consortium database, in 76 unrelated Pakistani exomes, or in 720 Pakistani control chromosomes. Both DNA variants affect highly conserved residues of S1PR2 and are predicted to be damaging by multiple bioinformatics tools. Molecular modeling predicts that these variants affect binding of sphingosine-1-phosphate (p.Arg108Pro) and G protein docking (p.Tyr140Cys). In the previously reported S1pr2(-/-) mice, stria vascularis abnormalities, organ of Corti degeneration, and profound hearing loss were~observed. Additionally, hair cell defects were seen in both knockout mice and morphant zebrafish. Family PKDF1400 presents with ARNSHI, which is consistent with the lack of gross malformations in S1pr2(-/-) mice, whereas family DEM4154 has lower limb malformations in addition to hearing loss. Our findings suggest the possibility of developing therapies against hair cell damage (e.g., from ototoxic drugs) through targeted stimulation of S1PR2.

}, keywords = {Amino Acid Sequence, Asian Continental Ancestry Group, Chromosomes, Human, Pair 19, Exome, Genes, Recessive, Hearing Loss, Humans, Lod Score, Logistic Models, Lysophospholipids, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Pedigree, Phenotype, Receptors, Lysosphingolipid, Sphingosine}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.12.004}, author = {Santos-Cortez, Regie Lyn P and Faridi, Rabia and Rehman, Atteeq U and Lee, Kwanghyuk and Ansar, Muhammad and Wang, Xin and Morell, Robert J and Isaacson, Rivka and Belyantseva, Inna A and Dai, Hang and Acharya, Anushree and Qaiser, Tanveer A and Muhammad, Dost and Ali, Rana Amjad and Shams, Sulaiman and Hassan, Muhammad Jawad and Shahzad, Shaheen and Raza, Syed Irfan and Bashir, Zil-E-Huma and Smith, Joshua D and Nickerson, Deborah A and Bamshad, Michael J and Riazuddin, Sheikh and Ahmad, Wasim and Friedman, Thomas B and Leal, Suzanne M} } @article {24, title = {Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in Humans.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Oct 06}, pages = {886-893}, abstract = {

Disruption of the establishment of left-right (L-R) asymmetry leads to situs anomalies ranging from situs inversus totalis (SIT) to situs ambiguus (heterotaxy). The genetic causes of laterality defects in humans are highly heterogeneous. Via whole-exome sequencing (WES), we identified homozygous mutations in PKD1L1 from three affected individuals in two unrelated families. PKD1L1 encodes a polycystin-1-like protein and its loss of function is known to cause laterality defects in mouse and medaka fish models. Family 1 had one fetus and one deceased child with heterotaxy and complex congenital heart malformations. WES identified a homozygous splicing mutation, c.6473+2_6473+3delTG, which disrupts the invariant splice donor site in intron 42, in both affected individuals. In the second family, a homozygous c.5072G>C (p.Cys1691Ser) missense mutation was detected in an individual with SIT and congenital heart disease. The p.Cys1691Ser substitution affects a highly conserved cysteine residue and is predicted by molecular modeling to disrupt a disulfide bridge essential for the proper folding of the G protein-coupled receptor proteolytic site (GPS) motif. Damaging effects associated with substitutions of this conserved cysteine residue in the GPS motif have also been reported in other genes, namely GPR56, BAI3, and PKD1 in human and lat-1 in C.~elegans, further supporting the likely pathogenicity of p.Cys1691Ser in PKD1L1. The identification of bi-allelic PKD1L1 mutations recapitulates previous findings regarding phenotypic consequences of loss of function of the orthologous genes in mice and medaka fish and further expands our understanding of genetic contributions to laterality defects in humans.

}, keywords = {Alleles, Amino Acid Motifs, Amino Acid Sequence, Animals, Caenorhabditis elegans, Cysteine, Exome, Female, Fetal Diseases, Functional Laterality, Heart Defects, Congenital, Heterotaxy Syndrome, Homozygote, Humans, Infant, Newborn, Introns, Male, Membrane Proteins, Mice, Middle Aged, Models, Molecular, Mutation, Mutation, Missense, Oryzias, Pedigree, RNA Splicing, Situs Inversus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.07.011}, author = {Vetrini, Francesco and D{\textquoteright}Alessandro, Lisa C A and Akdemir, Zeynep C and Braxton, Alicia and Azamian, Mahshid S and Eldomery, Mohammad K and Miller, Kathryn and Kois, Chelsea and Sack, Virginia and Shur, Natasha and Rijhsinghani, Asha and Chandarana, Jignesh and Ding, Yan and Holtzman, Judy and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Eng, Christine M and Hanchard, Neil A and Harel, Tamar and Rosenfeld, Jill A and Belmont, John W and Lupski, James R and Yang, Yaping} } @article {342, title = {MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Dec 01}, pages = {1229-1244}, abstract = {

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

}, keywords = {Basal Ganglia, Cells, Cultured, Child, Child, Preschool, Dystonic Disorders, Fatty Acids, Female, Fibroblasts, Genetic Complementation Test, Humans, Infant, Male, Mitochondria, Mitochondrial Diseases, Models, Molecular, Mutation, Mutation, Missense, Optic Atrophy, Oxidoreductases Acting on CH-CH Group Donors, Pedigree, RNA Splice Sites, Saccharomyces cerevisiae}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.09.021}, author = {Heimer, Gali and Ker{\"a}t{\"a}r, Juha M and Riley, Lisa G and Balasubramaniam, Shanti and Eyal, Eran and Pietik{\"a}inen, Laura P and Hiltunen, J Kalervo and Marek-Yagel, Dina and Hamada, Jeffrey and Gregory, Allison and Rogers, Caleb and Hogarth, Penelope and Nance, Martha A and Shalva, Nechama and Veber, Alvit and Tzadok, Michal and Nissenkorn, Andreea and Tonduti, Davide and Renaldo, Florence and Kraoua, Ichraf and Panteghini, Celeste and Valletta, Lorella and Garavaglia, Barbara and Cowley, Mark J and Gayevskiy, Velimir and Roscioli, Tony and Silberstein, Jonathon M and Hoffmann, Chen and Raas-Rothschild, Annick and Tiranti, Valeria and Anikster, Yair and Christodoulou, John and Kastaniotis, Alexander J and Ben-Zeev, Bruria and Hayflick, Susan J} } @article {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 {152, title = {Rare A2ML1 variants confer susceptibility to otitis media.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Aug}, pages = {917-20}, abstract = {

A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.

}, keywords = {alpha-Macroglobulins, Animals, Base Sequence, Child, Cochlea, Exome, Family Health, Female, Gene Duplication, Gene Frequency, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Male, Mice, Inbred C57BL, Models, Molecular, Otitis Media, Pedigree, Principal Component Analysis, Protein Conformation, Sequence Analysis, DNA}, issn = {1546-1718}, doi = {10.1038/ng.3347}, author = {Santos-Cortez, Regie Lyn P and Chiong, Charlotte M and Reyes-Quintos, Ma Rina T and Tantoco, Ma Leah C and Wang, Xin and Acharya, Anushree and Abbe, Izoduwa and Giese, Arnaud P and Smith, Joshua D and Allen, E Kaitlynn and Li, Biao and Cutiongco-de la Paz, Eva Maria and Garcia, Marieflor Cristy and Llanes, Erasmo Gonzalo D V and Labra, Patrick John and Gloria-Cruz, Teresa Luisa I and Chan, Abner L and Wang, Gao T and Daly, Kathleen A and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Patel, Janak A and Riazuddin, Saima and Sale, Michele M and Chonmaitree, Tasnee and Ahmed, Zubair M and Abes, Generoso T and Leal, Suzanne M} } @article {252, title = {CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration.}, journal = {Cell}, volume = {157}, year = {2014}, month = {2014 Apr 24}, pages = {651-63}, abstract = {

Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans.

}, keywords = {Animals, Brain, Cerebellum, Cleavage And Polyadenylation Specificity Factor, Female, Humans, Male, Mice, Models, Molecular, Neurodegenerative Diseases, Nuclear Proteins, Pedigree, Phosphotransferases, RNA Splicing, RNA, Transfer, Saccharomyces cerevisiae, Transcription Factors, Zebrafish, Zebrafish Proteins}, issn = {1097-4172}, doi = {10.1016/j.cell.2014.03.049}, author = {Schaffer, Ashleigh E and Eggens, Veerle R C and {\c C}a{\u g}layan, Ahmet Okay and Reuter, Miriam S and Scott, Eric and Coufal, Nicole G and Silhavy, Jennifer L and Xue, Yuanchao and Kayserili, H{\"u}lya and Yasuno, Katsuhito and Rosti, Rasim Ozgur and Abdellateef, Mostafa and Caglar, Caner and Kasher, Paul R and Cazemier, J Leonie and Weterman, Marian A and Cantagrel, Vincent and Cai, Na and Zweier, Christiane and Altunoglu, Umut and Satkin, N Bilge and Aktar, Fesih and Tuysuz, Beyhan and Yalcinkaya, Cengiz and Caksen, Huseyin and Bilguvar, Kaya and Fu, Xiang-Dong and Trotta, Christopher R and Gabriel, Stacey and Reis, Andr{\'e} and G{\"u}nel, Murat and Baas, Frank and Gleeson, Joseph G} } @article {311, title = {Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration.}, journal = {Proc Natl Acad Sci U S A}, volume = {110}, year = {2013}, month = {2013 Feb 26}, pages = {3489-94}, abstract = {

Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific de-ubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Through homozygosity mapping of the affected individuals followed by whole-exome sequencing of the index case, we identified a previously undescribed homozygous missense mutation within the ubiquitin binding domain of UCHL1 (UCHL1(GLU7ALA)), shared by all affected subjects. As demonstrated by isothermal titration calorimetry, purified UCHL1(GLU7ALA), compared with WT, exhibited at least sevenfold reduced affinity for ubiquitin. In vitro, the mutation led to a near complete loss of UCHL1 hydrolase activity. The GLU7ALA variant is predicted to interfere with the substrate binding by restricting the proper positioning of the substrate for tunneling underneath the cross-over loop spanning the catalytic cleft of UCHL1. This interference with substrate binding, combined with near complete loss of hydrolase activity, resulted in a >100-fold reduction in the efficiency of UCHL1(GLU7ALA) relative to WT. These findings demonstrate a broad requirement of UCHL1 in the maintenance of the nervous system.

}, keywords = {Adult, Age of Onset, Amino Acid Sequence, Base Sequence, Child, Preschool, Exome, Female, Genes, Recessive, Homozygote, Humans, Hydrolysis, Male, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Nerve Degeneration, Neurons, Pedigree, Protein Binding, Sequence Analysis, DNA, Substrate Specificity, Syndrome, Thermodynamics, Ubiquitin, Ubiquitin Thiolesterase}, issn = {1091-6490}, doi = {10.1073/pnas.1222732110}, author = {Bilguvar, Kaya and Tyagi, Navneet K and Ozkara, Cigdem and Tuysuz, Beyhan and Bakircioglu, Mehmet and Choi, Murim and Delil, Sakir and {\c C}a{\u g}layan, Ahmet O and Baranoski, Jacob F and Erturk, Ozdem and Yalcinkaya, Cengiz and Karacorlu, Murat and Dincer, Alp and Johnson, Michele H and Mane, Shrikant and Chandra, Sreeganga S and Louvi, Angeliki and Boggon, Titus J and Lifton, Richard P and Horwich, Arthur L and G{\"u}nel, Murat} } @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} }