@article {431, title = {Genetic analysis of CHARGE syndrome identifies overlapping molecular biology.}, journal = {Genet Med}, volume = {20}, year = {2018}, month = {2018 09}, pages = {1022-1029}, abstract = {

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

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

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

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

}, keywords = {Adolescent, Adult, Carrier Proteins, CHARGE Syndrome, Child, Child, Preschool, Cohort Studies, DNA Helicases, DNA-Binding Proteins, E1A-Associated p300 Protein, Epigenesis, Genetic, Female, Genetic Testing, Humans, Infant, Male, Mutation, Neoplasm Proteins, Phenotype, Repressor Proteins, RNA Splicing Factors}, issn = {1530-0366}, doi = {10.1038/gim.2017.233}, author = {Moccia, Amanda and Srivastava, Anshika and Skidmore, Jennifer M and Bernat, John A and Wheeler, Marsha and Chong, Jessica X and Nickerson, Deborah and Bamshad, Michael and Hefner, Margaret A and Martin, Donna M and Bielas, Stephanie L} } @article {412, title = {DUOX2 Gene Mutation Manifesting as Resistance to Thyrotropin Phenotype.}, journal = {Thyroid}, volume = {27}, year = {2017}, month = {2017 01}, pages = {129-131}, abstract = {

Resistance to thyrotropin (TSH) (RTSH; defined by elevated TSH and a normal or hypoplastic thyroid gland) can be caused by mutations in genes encoding the TSH receptor and PAX8, and it has been linked to a locus on chromosome 15. In two nonconsanguineous families with nongoitrous euthyroid hyperthyrotropinemia, typical of the RTSH phenotype, exome analysis identified five rare DUOX2 gene variants (p.A649E, p.P1391A, p.R885L, p.G488R, and p.SF965-6SfsX29) found to be pathogenic. This form of nongoitrous dyshormonogenesis masquerades both clinically and biochemically as RTSH. Accordingly, mutations in DUOX2 should be added to those of SLC26A4 as causes of RTSH.

}, keywords = {Child, Preschool, Congenital Hypothyroidism, Dual Oxidases, Female, Genotype, Humans, Male, Mutation, Pedigree, Phenotype, Thyroid Hormone Resistance Syndrome, Thyrotropin}, issn = {1557-9077}, doi = {10.1089/thy.2016.0469}, author = {Srichomkwun, Panudda and Takamatsu, Junta and Nickerson, Deborah A and Bamshad, Michael J and Chong, Jessica X and Refetoff, Samuel} } @article {349, title = {A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGFβ signaling and cause autosomal dominant spondylocarpotarsal synostosis.}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 02 16}, pages = {41803}, abstract = {

Spondylocarpotarsal synostosis (SCT) is a skeletal disorder characterized by progressive vertebral, carpal and tarsal fusions, and mild short stature. The majority of affected individuals have an autosomal recessive form of SCT and are homozygous or compound heterozygous for nonsense mutations in the gene that encodes the cytoskeletal protein filamin B (FLNB), but a subset do not have FLNB mutations. Exome sequence analysis of three SCT patients negative for FLNB mutations identified an autosomal dominant form of the disease due to heterozygosity for missense or nonsense mutations in MYH3, which encodes embryonic myosin. Cells transfected with the MYH3 missense mutations had reduced TGFβ signaling, revealing a regulatory role for embryonic myosin in the TGFβ signaling pathway. In wild-type mice, there was persistent postnatal expression of embryonic myosin in the small muscles joining the neural arches of the spine suggesting that loss of myosin function in these muscles contribute to the disease. Our findings demonstrate that dominant mutations in MYH3 underlie autosomal dominant SCT, identify a postnatal role for embryonic myosin and suggest that altered regulation of signal transduction in the muscles within the spine may lead to the development of vertebral fusions.

}, keywords = {Abnormalities, Multiple, Alleles, Bone Morphogenetic Proteins, Cytoskeletal Proteins, Female, Genes, Dominant, Genotype, Humans, Lumbar Vertebrae, Male, Musculoskeletal Diseases, Mutation, Myosins, Phenotype, Radiography, Scoliosis, Signal Transduction, Synostosis, Thoracic Vertebrae, Transforming Growth Factor beta, Whole Exome Sequencing}, issn = {2045-2322}, doi = {10.1038/srep41803}, author = {Zieba, Jennifer and Zhang, Wenjuan and Chong, Jessica X and Forlenza, Kimberly N and Martin, Jorge H and Heard, Kelly and Grange, Dorothy K and Butler, Merlin G and Kleefstra, Tjitske and Lachman, Ralph S and Nickerson, Deborah and Regnier, Michael and Cohn, Daniel H and Bamshad, Michael and Krakow, Deborah} } @article {105, title = {Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features.}, journal = {Genet Med}, volume = {18}, year = {2016}, month = {2016 08}, pages = {788-95}, abstract = {

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

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

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

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

}, keywords = {Child, Child, Preschool, Databases, Factual, Developmental Disabilities, Female, Genetic Association Studies, Histone Demethylases, Humans, Information Dissemination, Male, Mutation, Missense, Phenotype, Social Networking, Web Browser}, issn = {1530-0366}, doi = {10.1038/gim.2015.161}, author = {Chong, Jessica X and Yu, Joon-Ho and Lorentzen, Peter and Park, Karen M and Jamal, Seema M and Tabor, Holly K and Rauch, Anita and Saenz, Margarita Sifuentes and Boltshauser, Eugen and Patterson, Karynne E and Nickerson, Deborah A and Bamshad, Michael J} } @article {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} }