@article {515, title = {Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 03}, pages = {663-675}, abstract = {

PURPOSE: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants~in known and candidate cohesinopathy genes from a clinical exome perspective.

METHODS: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization.

RESULTS: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS.

CONCLUSION: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

}, keywords = {Adolescent, Alleles, Antigens, Nuclear, Biological Variation, Population, Carrier Proteins, Cell Cycle Proteins, Child, Child, Preschool, Chromosomal Proteins, Non-Histone, Cohort Studies, De Lange Syndrome, Exome, Female, Gene Frequency, Genetic Heterogeneity, Humans, INDEL Mutation, Male, Mutation, Nuclear Proteins, Phenotype, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins, Retrospective Studies, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-018-0085-6}, author = {Yuan, Bo and Neira, Juanita and Pehlivan, Davut and Santiago-Sim, Teresa and Song, Xiaofei and Rosenfeld, Jill and Posey, Jennifer E and Patel, Vipulkumar and Jin, Weihong and Adam, Margaret P and Baple, Emma L and Dean, John and Fong, Chin-To and Hickey, Scott E and Hudgins, Louanne and Leon, Eyby and Madan-Khetarpal, Suneeta and Rawlins, Lettie and Rustad, Cecilie F and Stray-Pedersen, Asbj{\o}rg and Tveten, Kristian and Wenger, Olivia and Diaz, Jullianne and Jenkins, Laura and Martin, Laura and McGuire, Marianne and Pietryga, Marguerite and Ramsdell, Linda and Slattery, Leah and Abid, Farida and Bertuch, Alison A and Grange, Dorothy and Immken, LaDonna and Schaaf, Christian P and Van Esch, Hilde and Bi, Weimin and Cheung, Sau Wai and Breman, Amy M and Smith, Janice L and Shaw, Chad and Crosby, Andrew H and Eng, Christine and Yang, Yaping and Lupski, James R and Xiao, Rui and Liu, Pengfei} } @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} }