@article {912, title = {Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 07}, pages = {1215-1226}, abstract = {

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.

METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.

RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.

CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

}, keywords = {Exome, Germ Cells, Humans, Intellectual Disability, Mutation, Missense, Phenotype, Transcriptome, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins}, issn = {1530-0366}, doi = {10.1038/s41436-020-0792-7}, author = {Castilla-Vallmanya, Laura and Selmer, Kaja K and Dimartino, Cl{\'e}mantine and Rabionet, Raquel and Blanco-S{\'a}nchez, Bernardo and Yang, Sandra and Reijnders, Margot R F and van Essen, Antonie J and Oufadem, Myriam and Vigeland, Magnus D and Stadheim, Barbro and Houge, Gunnar and Cox, Helen and Kingston, Helen and Clayton-Smith, Jill and Innis, Jeffrey W and Iascone, Maria and Cereda, Anna and Gabbiadini, Sara and Chung, Wendy K and Sanders, Victoria and Charrow, Joel and Bryant, Emily and Millichap, John and Vitobello, Antonio and Thauvin, Christel and Mau-Them, Frederic Tran and Faivre, Laurence and Lesca, Gaetan and Labalme, Audrey and Rougeot, Christelle and Chatron, Nicolas and Sanlaville, Damien and Christensen, Katherine M and Kirby, Amelia and Lewandowski, Raymond and Gannaway, Rachel and Aly, MAH and Lehman, Anna and Clarke, Lorne and Graul-Neumann, Luitgard and Zweier, Christiane and Lessel, Davor and Lozic, Bernarda and Aukrust, Ingvild and Peretz, Ryan and Stratton, Robert and Smol, Thomas and Dieux-Co{\"e}slier, Anne and Meira, Joanna and Wohler, Elizabeth and Sobreira, Nara and Beaver, Erin M and Heeley, Jennifer and Briere, Lauren C and High, Frances A and Sweetser, David A and Walker, Melissa A and Keegan, Catherine E and Jayakar, Parul and Shinawi, Marwan and Kerstjens-Frederikse, Wilhelmina S and Earl, Dawn L and Siu, Victoria M and Reesor, Emma and Yao, Tony and Hegele, Robert A and Vaske, Olena M and Rego, Shannon and Shapiro, Kevin A and Wong, Brian and Gambello, Michael J and McDonald, Marie and Karlowicz, Danielle and Colombo, Roberto and Serretti, Alessandro and Pais, Lynn and O{\textquoteright}Donnell-Luria, Anne and Wray, Alison and Sadedin, Simon and Chong, Belinda and Tan, Tiong Y and Christodoulou, John and White, Susan M and Slavotinek, Anne and Barbouth, Deborah and Morel Swols, Dayna and Parisot, M{\'e}lanie and Bole-Feysot, Christine and Nitschk{\'e}, Patrick and Pingault, V{\'e}ronique and Munnich, Arnold and Cho, Megan T and Cormier-Daire, Val{\'e}rie and Balcells, Susanna and Lyonnet, Stanislas and Grinberg, Daniel and Amiel, Jeanne and Urreizti, Roser and Gordon, Christopher T} } @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 {595, title = {Insights into genetics, human biology and disease gleaned from family based genomic studies.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 04}, pages = {798-812}, abstract = {

Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75\% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in~novel "disease gene" discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.

}, keywords = {Databases, Genetic, Genetic Diseases, Inborn, Genetic Heterogeneity, Genetic Predisposition to Disease, Genome, Human, Genomics, Humans, National Institutes of Health (U.S.), Pedigree, United States, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-018-0408-7}, author = {Posey, Jennifer E and O{\textquoteright}Donnell-Luria, Anne H and Chong, Jessica X and Harel, Tamar and Jhangiani, Shalini N and Coban Akdemir, Zeynep H and Buyske, Steven and Pehlivan, Davut and Carvalho, Claudia M B and Baxter, Samantha and Sobreira, Nara and Liu, Pengfei and Wu, Nan and Rosenfeld, Jill A and Kumar, Sushant and Avramopoulos, Dimitri and White, Janson J and Doheny, Kimberly F and Witmer, P Dane and Boehm, Corinne and Sutton, V Reid and Muzny, Donna M and Boerwinkle, Eric and G{\"u}nel, Murat and Nickerson, Deborah A and Mane, Shrikant and MacArthur, Daniel G and Gibbs, Richard A and Hamosh, Ada and Lifton, Richard P and Matise, Tara C and Rehm, Heidi L and Gerstein, Mark and Bamshad, Michael J and Valle, David and Lupski, James R} } @article {566, title = {ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 01}, pages = {42-50}, abstract = {

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2\%) that frequently presents with ascending aortic aneurysm (AscAA). BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for <=1\% of nonsyndromic BAV cases with and without AscAA, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

}, keywords = {Animals, Aortic Aneurysm, Thoracic, Aortic Valve, Cells, Cultured, Disease Models, Animal, Endothelial Cells, Female, Heart Valve Diseases, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Phenotype, Receptors, Cell Surface, Zebrafish}, issn = {1546-1718}, doi = {10.1038/s41588-018-0265-y}, author = {Gould, Russell A and Aziz, Hamza and Woods, Courtney E and Seman-Senderos, Manuel Alejandro and Sparks, Elizabeth and Preuss, Christoph and W{\"u}nnemann, Florian and Bedja, Djahida and Moats, Cassandra R and McClymont, Sarah A and Rose, Rebecca and Sobreira, Nara and Ling, Hua and MacCarrick, Gretchen and Kumar, Ajay Anand and Luyckx, Ilse and Cannaerts, Elyssa and Verstraeten, Aline and Bj{\"o}rk, Hanna M and Lehsau, Ann-Cathrin and Jaskula-Ranga, Vinod and Lauridsen, Henrik and Shah, Asad A and Bennett, Christopher L and Ellinor, Patrick T and Lin, Honghuang and Isselbacher, Eric M and Lino Cardenas, Christian Lacks and Butcher, Jonathan T and Hughes, G Chad and Lindsay, Mark E and Mertens, Luc and Franco-Cereceda, Anders and Verhagen, Judith M A and Wessels, Marja and Mohamed, Salah A and Eriksson, Per and Mital, Seema and Van Laer, Lut and Loeys, Bart L and Andelfinger, Gregor and McCallion, Andrew S and Dietz, Harry C} } @article {629, title = {A novel pathogenic variant in a family with paroxysmal kinesigenic dyskinesia and benign familial infantile seizures.}, journal = {Cold Spring Harb Mol Case Stud}, volume = {4}, year = {2018}, month = {2018 02}, abstract = {

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

}, keywords = {Amino Acid Sequence, Base Sequence, Child, Chromosome Segregation, Conserved Sequence, Dystonia, Epilepsy, Benign Neonatal, Evolution, Molecular, Family, Female, Humans, Infant, Inheritance Patterns, Male, Membrane Proteins, Mutation, Nerve Tissue Proteins, Pedigree}, issn = {2373-2873}, doi = {10.1101/mcs.a002287}, author = {Lu, Jacqueline G and Bishop, Juliet and Cheyette, Sarah and Zhulin, Igor B and Guo, Su and Sobreira, Nara and Brenner, Steven E} } @article {422, title = {Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {815-823}, abstract = {

Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo~FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70~kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.

}, keywords = {Adolescent, Adult, Bone and Bones, Bone Diseases, Developmental, Cartilage, Child, Child, Preschool, Exome, Female, Fibronectins, Fractures, Bone, Humans, Male, Mutation, Osteochondrodysplasias, Phenotype, Scoliosis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.019}, author = {Lee, Chae Syng and Fu, He and Baratang, Nissan and Rousseau, Justine and Kumra, Heena and Sutton, V Reid and Niceta, Marcello and Ciolfi, Andrea and Yamamoto, Guilherme and Bertola, D{\'e}bora and Marcelis, Carlo L and Lugtenberg, Dorien and Bartuli, Andrea and Kim, Choel and Hoover-Fong, Julie and Sobreira, Nara and Pauli, Richard and Bacino, Carlos and Krakow, Deborah and Parboosingh, Jillian and Yap, Patrick and Kariminejad, Ariana and McDonald, Marie T and Aracena, Mariana I and Lausch, Ekkehart and Unger, Sheila and Superti-Furga, Andrea and Lu, James T and Cohn, Dan H and Tartaglia, Marco and Lee, Brendan H and Reinhardt, Dieter P and Campeau, Philippe M} } @article {396, title = {A novel mutation in GMPPA in siblings with apparent intellectual disability, epilepsy, dysmorphism, and autonomic dysfunction.}, journal = {Am J Med Genet A}, volume = {173}, year = {2017}, month = {2017 Aug}, pages = {2246-2250}, abstract = {

GMPPA encodes the GDP-mannose pyrophosphorylase A protein (GMPPA). The function of GMPPA is not well defined, however it is a homolog of GMPPB which catalyzes the reaction that converts mannose-1-phosphate and guanosine-5{\textquoteright}-triphosphate to GDP-mannose. Previously, biallelic mutations in GMPPA were reported to cause a disorder characterized by achalasia, alacrima, neurological deficits, and intellectual disability. In this study, we report a female proband with achalasia, alacrima, hypohydrosis, apparent intellectual disability, seizures, microcephaly, esotropia, and craniofacial dysmorphism. Exome sequencing identified a previously unreported homozygous c.853+1G>A variant in GMPPA in the proband and her affected sister. Their unaffected parents were heterozygous, and unaffected brother homozygous wild type for this variant. Lymphoblast cells from the affected sisters showed complete loss of the GMPPA protein by Western blotting, and increased levels of GDP-mannose in lymphoblasts on high performance liquid chromatography. Based on our findings and the previous report describing patients with an overlapping phenotype, we conclude that this novel variant in GMPPA, identified by exome sequencing in the proband and her affected sister, is the genetic cause of their phenotype and may expand the known phenotype of this recently described glycosylation disorder.

}, keywords = {Abnormalities, Multiple, Child, Child, Preschool, Craniofacial Abnormalities, Epilepsy, Exome, Facies, Female, Heterozygote, Humans, Intellectual Disability, Microcephaly, Muscular Atrophy, Mutation, Missense, Nucleotidyltransferases, Pedigree, Phenotype, Seizures}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38292}, author = {Gold, Wendy A and Sobreira, Nara and Wiame, Elsa and Marbaix, Alexandre and Van Schaftingen, Emile and Franzka, Patricia and Riley, Lisa G and Worgan, Lisa and H{\"u}bner, Christian A and Christodoulou, John and Ad{\`e}s, Lesley C} } @article {433, title = {Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities.}, journal = {Eur J Hum Genet}, volume = {25}, year = {2017}, month = {2017 12}, pages = {1335-1344}, abstract = {

Kabuki syndrome is a monogenic disorder caused by loss of function variants in either of two genes encoding histone-modifying enzymes. We performed targeted sequencing in a cohort of 27 probands with a clinical diagnosis of Kabuki syndrome. Of these, 12 had causative variants in the two known Kabuki syndrome genes. In 2, we identified presumptive loss of function de novo variants in KMT2A (missense and splice site variants), a gene that encodes another histone modifying enzyme previously exclusively associated with Wiedermann-Steiner syndrome. Although Kabuki syndrome is a disorder of histone modification, we also find alterations in DNA methylation among individuals with a Kabuki syndrome diagnosis relative to matched normal controls, regardless of whether they carry a variant in KMT2A or KMT2D or not. Furthermore, we observed characteristic global abnormalities of DNA methylation that distinguished patients with a loss of function variant in KMT2D or missense or splice site variants in either KMT2D or KMT2A from normal controls. Our results provide new insights into the relationship of genotype to epigenotype and phenotype and indicate cross-talk between histone and DNA methylation machineries exposed by inborn errors of the epigenetic apparatus.

}, keywords = {Abnormalities, Multiple, Case-Control Studies, Child, DNA Methylation, Face, Female, Hematologic Diseases, Histone-Lysine N-Methyltransferase, Humans, Loss of Function Mutation, Male, Myeloid-Lymphoid Leukemia Protein, Phenotype, Vestibular Diseases}, issn = {1476-5438}, doi = {10.1038/s41431-017-0023-0}, author = {Sobreira, Nara and Brucato, Martha and Zhang, Li and Ladd-Acosta, Christine and Ongaco, Chrissie and Romm, Jane and Doheny, Kimberly F and Mingroni-Netto, Regina C and Bertola, D{\'e}bora and Kim, Chong A and Perez, Ana Ba and Melaragno, Maria I and Valle, David and Meloni, Vera A and Bjornsson, Hans T} } @article {417, title = {Exome sequencing identifies a de novo frameshift mutation in the imprinted gene ZDBF2 in a sporadic patient with Nasopalpebral Lipoma-coloboma syndrome.}, journal = {Am J Med Genet A}, volume = {170}, year = {2016}, month = {2016 07}, pages = {1934-7}, abstract = {

Nasopalpebral lipoma-coloboma syndrome (NPLCS, OMIM\%167730) is an uncommon malformation entity with autosomal dominant inheritance characterized by the combination of nasopalpebral lipoma, colobomas in upper and lower eyelids, telecanthus, and maxillary hypoplasia. To date, no genetic defects have been associated with familial or sporadic NPLCS cases and the etiology of the disease remains unknown. In this work, the results of whole exome sequencing in a sporadic NPLCS patient are presented. Exome sequencing identified a de novo heterozygous frameshift dinucleotide insertion c.6245_6246 insTT (p.His2082fs*67) in ZDBF2 (zinc finger, DBF-type containing 2), a gene located at 2q33.3. This variant was absent in parental DNA, in a set of 300 ethnically matched controls, and in public exome variant databases. This is the first genetic variant identified in a NPLCS patient and evidence supporting the pathogenicity of the identified mutation is discussed. {\textcopyright} 2016 Wiley Periodicals, Inc.

}, keywords = {Abnormalities, Multiple, Base Sequence, Child, Preschool, Coloboma, DNA-Binding Proteins, Exome, Eyelid Neoplasms, Female, Frameshift Mutation, Genomic Imprinting, Humans, Lipoma, Pedigree}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37683}, author = {Chac{\'o}n-Camacho, Oscar F and Sobreira, Nara and You, Jing and Pi{\~n}a-Aguilar, Raul E and Villegas-Ruiz, Vanessa and Zenteno, Juan C} } @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 {126, title = {Gonadal mosaicism in ARID1B gene causes intellectual disability and dysmorphic features in three siblings.}, journal = {Am J Med Genet A}, volume = {170A}, year = {2016}, month = {2016 Jan}, pages = {156-61}, abstract = {

The gene encoding the AT-rich interaction domain-containing protein 1B (ARID1B) has recently been shown to be one of the most frequently mutated genes in patients with intellectual disability (ID). The phenotypic spectrums associated with variants in this gene vary widely ranging for mild to severe non-specific ID to Coffin-Siris syndrome. In this study, we evaluated three children from a consanguineous Emirati family affected with ID and dysmorphic features. Genomic DNA from all affected siblings was analyzed using CGH array and whole-exome sequencing (WES). Based on a recessive mode of inheritance, homozygous or compound heterozygous variants shared among all three affected children could not be identified. However, further analysis revealed a heterozygous variant (c.4318C>T; p.Q1440*) in the three affected children in an autosomal dominant ID causing gene, ARID1B. This variant was absent in peripheral blood samples obtained from both parents and unaffected siblings. Therefore, we propose that the most likely explanation for this situation is that one of the parents is a gonadal mosaic for the variant. To the best of our knowledge, this is the first report of a gonadal mosaicism inheritance of an ARID1B variant leading to familial ID recurrence.

}, keywords = {Abnormalities, Multiple, Adolescent, Child, DNA-Binding Proteins, Exome, Face, Female, Hand Deformities, Congenital, Heterozygote, Humans, Intellectual Disability, Male, Micrognathism, Mosaicism, Mutation, Neck, Pedigree, Siblings, Transcription Factors}, issn = {1552-4833}, doi = {10.1002/ajmg.a.37405}, author = {Ben-Salem, Salma and Sobreira, Nara and Akawi, Nadia A and Al-Shamsi, Aisha M and John, Anne and Pramathan, Thachillath and Valle, David and Ali, Bassam R and Al-Gazali, Lihadh} } @article {73, title = {Two novel germline DDX41 mutations in a family with inherited myelodysplasia/acute myeloid leukemia.}, journal = {Haematologica}, volume = {101}, year = {2016}, month = {2016 06}, pages = {e228-31}, keywords = {DEAD-box RNA Helicases, Family, Female, Germ-Line Mutation, Humans, Leukemia, Myeloid, Acute, Male, Myelodysplastic Syndromes, Neoplasm Proteins}, issn = {1592-8721}, doi = {10.3324/haematol.2015.139790}, author = {Li, Ruijuan and Sobreira, Nara and Witmer, P Dane and Pratz, Keith W and Braunstein, Evan M} } @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 {413, title = {Whole-exome sequencing identifies novel variants in PNPT1 causing oxidative phosphorylation defects and severe multisystem disease.}, journal = {Eur J Hum Genet}, volume = {25}, year = {2016}, month = {2016 01}, pages = {79-84}, abstract = {

Recent advances in next-generation sequencing strategies have led to the discovery of many novel disease genes. We describe here a non-consanguineous family with two affected boys presenting with early onset of severe axonal neuropathy, optic atrophy, intellectual disability, auditory neuropathy and chronic respiratory and gut disturbances. Whole-exome sequencing (WES) was performed on all family members and we identified compound heterozygous variants (c.[760C>A];[1528G>C];p.[(Gln254Lys);(Ala510Pro)] in the polyribonucleotide nucleotidyltransferase 1 (PNPT1) gene in both affected individuals. PNPT1 encodes the polynucleotide phosphorylase (PNPase) protein, which is involved in the transport of small RNAs into the mitochondria. These RNAs are involved in the mitochondrial translation machinery, responsible for the synthesis of mitochondrially encoded subunits of the oxidative phosphorylation (OXPHOS) complexes. Both PNPT1 variants are within highly conserved regions and predicted to be damaging. These variants resulted in quaternary defects in the PNPase protein and a clear reduction in protein and mRNA expression of PNPT1 in patient fibroblasts compared with control cells. Protein analysis of the OXPHOS complexes showed a significant reduction in complex I (CI), complex III (CIII) and complex IV (CIV). Enzyme activity of CI and CIV was clearly reduced in patient fibroblasts compared with controls along with a 33\% reduction in total mitochondrial protein synthesis. In vitro rescue experiments, using exogenous expression of wild-type PNPT1 in patient fibroblasts, ameliorated the deficiencies in the OXPHOS complex protein expression, supporting the likely pathogenicity of these variants and the importance of WES in efficiently identifying rare genetic disease genes.

}, keywords = {Axons, Exome, Exoribonucleases, High-Throughput Nucleotide Sequencing, Humans, Intellectual Disability, Male, Mitochondria, Mutation, Optic Atrophy, Oxidative Phosphorylation, Pedigree, Protein Structure, Quaternary}, issn = {1476-5438}, doi = {10.1038/ejhg.2016.128}, author = {Alodaib, Ahmad and Sobreira, Nara and Gold, Wendy A and Riley, Lisa G and Van Bergen, Nicole J and Wilson, Meredith J and Bennetts, Bruce and Thorburn, David R and Boehm, Corinne and Christodoulou, John} } @article {641, title = {An anadysplasia-like, spontaneously remitting spondylometaphyseal dysplasia secondary to lamin B receptor (LBR) gene mutations: further definition of the phenotypic heterogeneity of LBR-bone dysplasias.}, journal = {Am J Med Genet A}, volume = {167A}, year = {2015}, month = {2015 Jan}, pages = {159-63}, abstract = {

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

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Mutation, Osteochondrodysplasias, Phenotype, Pregnancy, Radiography, Receptors, Cytoplasmic and Nuclear, Spine}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36808}, author = {Sobreira, Nara and Modaff, Peggy and Steel, Gary and You, Jing and Nanda, Sonia and Hoover-Fong, Julie and Valle, David and Pauli, Richard M} } @article {199, title = {Assessment of incidental findings in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics.}, journal = {Genet Med}, volume = {17}, year = {2015}, month = {2015 Oct}, pages = {782-8}, abstract = {

PURPOSE: In March 2013 the American College of Medical Genetics and Genomics published a list of 56 genes with the recommendation that pathogenic and likely pathogenic variants detected incidentally by clinical sequencing be reported to patients. As an initial step in determining the practical consequences of this recommendation in the research setting, we searched for variants in these genes in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics.

METHODS: We identified rare, nonsynonymous, and splicing single-nucleotide variants and insertions/deletions and assessed variant classification using the Human Gene Mutation, Emory, and ClinVar databases. We analyzed the burden of mutation in each of the 56 genes and determined which variants should be reported to patients.

RESULTS: Our filtering resulted in 249 distinct variants, with a mean of 1.69 variants per individual. Half of these were novel missense mutations not classified by any of the three reference databases. Of 101 variants listed in the Human Gene Mutation Database, 48 were also in ClinVar and 3 were also in Emory; half of these shared variants were classified discordantly between databases. Some genes consistently had greater variation than others. In total, 0.86\% of individuals had a reportable incidental variant.

CONCLUSION: These observations demonstrate some current challenges of assessing phenotypic consequences of incidental variants for counseling patients.

}, keywords = {Databases, Nucleic Acid, Exome, Female, Genetic Diseases, Inborn, Genomics, High-Throughput Nucleotide Sequencing, Humans, Incidental Findings, Male, Mutation, Polymorphism, Single Nucleotide}, issn = {1530-0366}, doi = {10.1038/gim.2014.196}, author = {Jurgens, Julie and Ling, Hua and Hetrick, Kurt and Pugh, Elizabeth and Schiettecatte, Fran{\c c}ois and Doheny, Kimberly and Hamosh, Ada and Avramopoulos, Dimitri and Valle, David and Sobreira, Nara} } @article {139, title = {GeneMatcher: a matching tool for connecting investigators with an interest in the same gene.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Oct}, pages = {928-30}, abstract = {

Here, we describe an overview and update on GeneMatcher (http://www.genematcher.org), a freely accessible Web-based tool developed as part of the Baylor-Hopkins Center for Mendelian Genomics. We created GeneMatcher with the goal of identifying additional individuals with rare phenotypes who had variants in the same candidate disease gene. We also wanted to facilitate connections to basic scientists working on orthologous genes in model systems with the goal of connecting their work to human Mendelian phenotypes. Meeting these goals will enhance the identification of novel Mendelian genes. Launched in September, 2013, GeneMatcher now has 2,178 candidate genes from 486 submitters spread across 38 countries entered in the database (June 1, 2015). GeneMatcher is also part of the Matchmaker Exchange (http://matchmakerexchange.org/) with an Application Programing Interface enabling submitters to query other databases of genetic variants and phenotypes without having to create accounts and data entries in multiple systems.

}, keywords = {Computational Biology, Databases, Genetic, Genetic Predisposition to Disease, Genetic Variation, Humans, Information Dissemination, Phenotype, Rare Diseases, Software, User-Computer Interface, Web Browser}, issn = {1098-1004}, doi = {10.1002/humu.22844}, author = {Sobreira, Nara and Schiettecatte, Fran{\c c}ois and Valle, David and Hamosh, Ada} } @article {146, title = {GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Oct}, pages = {1009-1014}, abstract = {

We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo frameshift (NM_002140.3: c.953+1dup), and the other with a de novo splice donor site variant (NM_002140.3: c.257G>A). Both probands have intellectual disability, a shared unique craniofacial phenotype, and connective tissue and skeletal abnormalities. The identification of this syndrome was made possible by a new online tool, GeneMatcher, which facilitates connections between clinicians and researchers based on shared interest in candidate genes. This report demonstrates that new Web-based approaches can be effective in helping investigators solve exome sequencing projects, and also highlights the newer paradigm of "reverse phenotyping," where characterization of syndromic features follows the identification of genetic variants.

}, keywords = {Abnormalities, Multiple, Adolescent, Child, Craniofacial Abnormalities, Databases, Genetic, Genetic Predisposition to Disease, Heterogeneous-Nuclear Ribonucleoprotein K, Humans, Information Dissemination, Intellectual Disability, Male, Muscular Atrophy, Phenotype, Polymorphism, Single Nucleotide, Ribonucleoproteins, Software, Web Browser}, issn = {1098-1004}, doi = {10.1002/humu.22837}, author = {Au, P Y Billie and You, Jing and Caluseriu, Oana and Schwartzentruber, Jeremy and Majewski, Jacek and Bernier, Francois P and Ferguson, Marcia and Valle, David and Parboosingh, Jillian S and Sobreira, Nara and Innes, A Micheil and Kline, Antonie D} } @article {149, title = {The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Aug 06}, pages = {199-215}, abstract = {

Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying \~{}50\% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.

}, keywords = {Genetic Diseases, Inborn, Genetics, Medical, Humans, Phenotype, Proteins}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.06.009}, author = {Chong, Jessica X and Buckingham, Kati J and Jhangiani, Shalini N and Boehm, Corinne and Sobreira, Nara and Smith, Joshua D and Harrell, Tanya M and McMillin, Margaret J and Wiszniewski, Wojciech and Gambin, Tomasz and Coban Akdemir, Zeynep H and Doheny, Kimberly and Scott, Alan F and Avramopoulos, Dimitri and Chakravarti, Aravinda and Hoover-Fong, Julie and Mathews, Debra and Witmer, P Dane and Ling, Hua and Hetrick, Kurt and Watkins, Lee and Patterson, Karynne E and Reinier, Frederic and Blue, Elizabeth and Muzny, Donna and Kircher, Martin and Bilguvar, Kaya and L{\'o}pez-Gir{\'a}ldez, Francesc and Sutton, V Reid and Tabor, Holly K and Leal, Suzanne M and G{\"u}nel, Murat and Mane, Shrikant and Gibbs, Richard A and Boerwinkle, Eric and Hamosh, Ada and Shendure, Jay and Lupski, James R and Lifton, Richard P and Valle, David and Nickerson, Deborah A and Bamshad, Michael J} } @article {142, title = {Identification and functional characterization of natural human melanocortin 1 receptor mutant alleles in Pakistani population.}, journal = {Pigment Cell Melanoma Res}, volume = {28}, year = {2015}, month = {2015 Nov}, pages = {730-5}, abstract = {

Melanocortin 1 receptor (MC1R), a Gs protein-coupled receptor of the melanocyte{\textquoteright}s plasma membrane, is a major determinant of skin pigmentation and phototype. Upon activation by α-melanocyte stimulating hormone, MC1R triggers the cAMP cascade to stimulate eumelanogenesis. We used whole-exome sequencing to identify causative alleles in Pakistani families with skin and hair hypopigmentation. Six MC1R mutations segregated with the phenotype in seven families, including a p.Val174del in-frame deletion and a p.Tyr298* nonsense mutation, that were analyzed for function in heterologous HEK293 cells. p.Tyr298* MC1R showed no agonist-induced signaling to the cAMP or ERK pathways, nor detectable agonist binding. Conversely, signaling was comparable for p.Val174del and wild-type in HEK cells overexpressing the proteins, but binding analysis suggested impaired cell surface expression. Flow cytometry and confocal imaging studies revealed reduced plasma membrane expression of p.Val174del and p.Tyr298*. Therefore, p.Tyr298* was a total loss-of-function (LOF) allele, while p.Val174del displayed a partial LOF attribute.

}, keywords = {Alleles, Family, Female, Humans, Hypopigmentation, Male, Mutation, Pakistan, Pedigree, Phenotype, Receptor, Melanocortin, Type 1}, issn = {1755-148X}, doi = {10.1111/pcmr.12400}, author = {Shahzad, Mohsin and Sires Campos, Julia and Tariq, Nabeela and Herraiz Serrano, Cecilia and Yousaf, Rizwan and Jim{\'e}nez-Cervantes, Celia and Yousaf, Sairah and Waryah, Yar M and Dad, Haseeb A and Blue, Elizabeth M and Sobreira, Nara and L{\'o}pez-Gir{\'a}ldez, Francesc and Kausar, Tasleem and Ali, Muhammad and Waryah, Ali M and Riazuddin, Saima and Shaikh, Rehan S and Garc{\'\i}a-Borr{\'o}n, Jos{\'e} C and Ahmed, Zubair M} } @article {136, title = {The Matchmaker Exchange API: automating patient matching through the exchange of structured phenotypic and genotypic profiles.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Oct}, pages = {922-7}, abstract = {

Despite the increasing prevalence of clinical sequencing, the difficulty of identifying additional affected families is a key obstacle to solving many rare diseases. There may only be a handful of similar patients worldwide, and their data may be stored in diverse clinical and research databases. Computational methods are necessary to enable finding similar patients across the growing number of patient repositories and registries. We present the Matchmaker Exchange Application Programming Interface (MME API), a protocol and data format for exchanging phenotype and genotype profiles to enable matchmaking among patient databases, facilitate the identification of additional cohorts, and increase the rate with which rare diseases can be researched and diagnosed. We designed the API to be straightforward and flexible in order to simplify its adoption on a large number of data types and workflows. We also provide a public test data set, curated from the literature, to facilitate implementation of the API and development of new matching algorithms. The initial version of the API has been successfully implemented by three members of the Matchmaker Exchange and was immediately able to reproduce previously identified matches and generate several new leads currently being validated. The API is available at https://github.com/ga4gh/mme-apis.

}, keywords = {Algorithms, Computational Biology, Databases, Genetic, Genetic Predisposition to Disease, Genotype, Humans, Information Dissemination, Phenotype, Rare Diseases, Web Browser}, issn = {1098-1004}, doi = {10.1002/humu.22850}, author = {Buske, Orion J and Schiettecatte, Fran{\c c}ois and Hutton, Benjamin and Dumitriu, Sergiu and Misyura, Andriy and Huang, Lijia and Hartley, Taila and Girdea, Marta and Sobreira, Nara and Mungall, Chris and Brudno, Michael} } @article {130, title = {Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Sep 03}, pages = {457-64}, abstract = {

Using whole-exome sequencing, we have identified in ten families 14 individuals with microcephaly, developmental delay, intellectual disability, hypotonia, spasticity, seizures, sensorineural hearing loss, cortical visual impairment, and rare autosomal-recessive predicted pathogenic variants in spermatogenesis-associated protein 5 (SPATA5). SPATA5 encodes a ubiquitously expressed member of the ATPase associated with diverse activities (AAA) protein family and is involved in mitochondrial morphogenesis during early spermatogenesis. It might also play a role in post-translational modification during cell differentiation in neuronal development. Mutations in SPATA5 might affect brain development and function, resulting in microcephaly, developmental delay, and intellectual disability.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, ATPases Associated with Diverse Cellular Activities, Base Sequence, Exome, Female, Gene Frequency, Genes, Recessive, Hearing Loss, Homeodomain Proteins, Humans, Intellectual Disability, Male, Microcephaly, Molecular Sequence Data, Mutation, Seizures, Sequence Alignment, Sequence Analysis, DNA}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.07.014}, author = {Tanaka, Akemi J and Cho, Megan T and Millan, Francisca and Juusola, Jane and Retterer, Kyle and Joshi, Charuta and Niyazov, Dmitriy and Garnica, Adolfo and Gratz, Edward and Deardorff, Matthew and Wilkins, Alisha and Ortiz-Gonzalez, Xilma and Mathews, Katherine and Panzer, Karin and Brilstra, Eva and van Gassen, Koen L I and Volker-Touw, Catharina M L and van Binsbergen, Ellen and Sobreira, Nara and Hamosh, Ada and McKnight, Dianalee and Monaghan, Kristin G and Chung, Wendy K} } @article {144, title = {Novel COL2A1 variant (c.619G>A, p.Gly207Arg) manifesting as a phenotype similar to progressive pseudorheumatoid dysplasia and spondyloepiphyseal dysplasia, Stanescu type.}, journal = {Hum Mutat}, volume = {36}, year = {2015}, month = {2015 Oct}, pages = {1004-8}, abstract = {

Progressive pseudorheumatoid dysplasia (PPRD) is a rare, autosomal-recessive condition characterized by mild spondyloepiphyseal dysplasia (SED) and severe, progressive, early-onset arthritis due to WISP3 mutations. SED, Stanescu type, is a vaguely delineated autosomal-dominant dysplasia of unknown genetic etiology. Here, we report three individuals from two unrelated families with radiological features similar to PPRD and SED, Stanescu type who share the same novel COL2A1 variant and were matched following discussion at an academic conference. In the first family, we performed whole-exome sequencing on three family members, two of whom have a PPRD-like phenotype, and identified a heterozygous variant (c.619G>A, p.Gly207Arg) in both affected individuals. Independently, targeted sequencing of the COL2A1 gene in an unrelated proband with a similar phenotype identified the same heterozygous variant. We suggest that the p.Gly207Arg variant causes a distinct type II collagenopathy with features of PPRD and SED, Stanescu type.

}, keywords = {Adolescent, Adult, Child, Collagen Type II, Exome, Female, Humans, Joint Diseases, Male, Osteochondrodysplasias, Pedigree, Polymorphism, Single Nucleotide, Radiography, Sequence Analysis, DNA}, issn = {1098-1004}, doi = {10.1002/humu.22839}, author = {Jurgens, Julie and Sobreira, Nara and Modaff, Peggy and Reiser, Catherine A and Seo, Soo Hyun and Seong, Moon-Woo and Park, Sung Sup and Kim, Ok Hwa and Cho, Tae-Joon and Pauli, Richard M} } @article {277, title = {DIAMUND: direct comparison of genomes to detect mutations.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Mar}, pages = {283-8}, abstract = {

DNA sequencing has become a powerful method to discover the genetic basis of disease. Standard, widely used protocols for analysis usually begin by comparing each individual to the human reference genome. When applied to a set of related individuals, this approach reveals millions of differences, most of which are shared among the individuals and unrelated to the disease being investigated. We have developed a novel algorithm for variant detection, one that compares DNA sequences directly to one another, without aligning them to the reference genome. When used to find de novo mutations in exome sequences from family trios, or to compare normal and diseased samples from the same individual, the new method, direct alignment for mutation discovery (DIAMUND), produces a dramatically smaller list of candidate mutations than previous methods, without losing sensitivity to detect the true cause of a genetic disease. We demonstrate our results on several example cases, including two family trios in which it correctly found the disease-causing variant while excluding thousands of harmless variants that standard methods had identified.

}, keywords = {Algorithms, Computational Biology, Exome, Genetic Loci, Genetic Variation, Genome, Human, Humans, Mutation, Sequence Alignment, Sequence Analysis, DNA, Software}, issn = {1098-1004}, doi = {10.1002/humu.22503}, author = {Salzberg, Steven L and Pertea, Mihaela and Fahrner, Jill A and Sobreira, Nara} } @article {275, title = {Mutations in PCYT1A, encoding a key regulator of phosphatidylcholine metabolism, cause spondylometaphyseal dysplasia with cone-rod dystrophy.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jan 02}, pages = {105-12}, keywords = {Alleles, Child, Preschool, Choline-Phosphate Cytidylyltransferase, Female, Humans, Infant, Male, Middle Aged, Mutation, Missense, Osteochondrodysplasias, Pedigree, Phosphatidylcholines, Retinitis Pigmentosa}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.11.018}, author = {Hoover-Fong, Julie and Sobreira, Nara and Jurgens, Julie and Modaff, Peggy and Blout, Carrie and Moser, Ann and Kim, Ok-Hwa and Cho, Tae-Joon and Cho, Sung Yoon and Kim, Sang Jin and Jin, Dong-Kyu and Kitoh, Hiroshi and Park, Woong-Yang and Ling, Hua and Hetrick, Kurt N and Doheny, Kimberly F and Valle, David and Pauli, Richard M} } @article {310, title = {PhenoDB: a new web-based tool for the collection, storage, and analysis of phenotypic features.}, journal = {Hum Mutat}, volume = {34}, year = {2013}, month = {2013 Apr}, pages = {566-71}, abstract = {

To interpret whole exome/genome sequence data for clinical and research purposes, comprehensive phenotypic information, knowledge of pedigree structure, and results of previous clinical testing are essential. With these requirements in mind and to meet the needs of the Centers for Mendelian Genomics project, we have developed PhenoDB (http://phenodb.net), a secure, Web-based portal for entry, storage, and analysis of phenotypic and other clinical information. The phenotypic features are organized hierarchically according to the major headings and subheadings of the Online Mendelian Inheritance in Man (OMIM{\textregistered}) clinical synopses, with further subdivisions according to structure and function. Every string allows for a free-text entry. All of the approximately 2,900 features use the preferred term from Elements of Morphology and are fully searchable and mapped to the Human Phenotype Ontology and Elements of Morphology. The PhenoDB allows for ascertainment of relevant information from a case in a family or cohort, which is then searchable by family, OMIM number, phenotypic feature, mode of inheritance, genes screened, and so on. The database can also be used to format phenotypic data for submission to dbGaP for appropriately consented individuals. PhenoDB was built using Django, an open source Web development tool, and is freely available through the Johns Hopkins McKusick-Nathans Institute of Genetic Medicine (http://phenodb.net).

}, keywords = {Databases, Factual, Genomics, Humans, Internet, Medical Informatics, Phenotype, Software}, issn = {1098-1004}, doi = {10.1002/humu.22283}, author = {Hamosh, Ada and Sobreira, Nara and Hoover-Fong, Julie and Sutton, V Reid and Boehm, Corinne and Schiettecatte, Fran{\c c}ois and Valle, David} }