Title | Insights into genetics, human biology and disease gleaned from family based genomic studies. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Posey, JE, O'Donnell-Luria, AH, Chong, JX, Harel, T, Jhangiani, SN, Akdemir, ZHCoban, Buyske, S, Pehlivan, D, Carvalho, CMB, Baxter, S, Sobreira, N, Liu, P, Wu, N, Rosenfeld, JA, Kumar, S, Avramopoulos, D, White, JJ, Doheny, KF, P Witmer, D, Boehm, C, V Sutton, R, Muzny, DM, Boerwinkle, E, Gunel, M, Nickerson, DA, Mane, S, MacArthur, DG, Gibbs, RA, Hamosh, A, Lifton, RP, Matise, TC, Rehm, HL, Gerstein, M, Bamshad, MJ, Valle, D, Lupski, JR |
Corporate Authors | Centers for Mendelian Genomics |
Journal | Genet Med |
Volume | 21 |
Issue | 4 |
Pagination | 798-812 |
Date Published | 2019 Apr |
ISSN | 1530-0366 |
Keywords | Databases, Genetic, Exome Sequencing, Genetic Diseases, Inborn, Genetic Heterogeneity, Genetic Predisposition to Disease, Genome, Human, Genomics, Humans, National Institutes of Health (U.S.), Pedigree, United States |
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. |
DOI | 10.1038/s41436-018-0408-7 |
Alternate Journal | Genet Med |
PubMed ID | 30655598 |
PubMed Central ID | PMC6691975 |
Grant List | UM1 HG008900 / HG / NHGRI NIH HHS / United States UM1 HG006504 / HG / NHGRI NIH HHS / United States K12 HD052896 / HD / NICHD NIH HHS / United States UM1 HG006542 / HG / NHGRI NIH HHS / United States R35 NS105078 / NS / NINDS NIH HHS / United States K08 HG008986 / HG / NHGRI NIH HHS / United States R03 HD092569 / HD / NICHD NIH HHS / United States UM1 HG006493 / HG / NHGRI NIH HHS / United States T32 GM008307 / GM / NIGMS NIH HHS / United States U24 HG008956 / HG / NHGRI NIH HHS / United States S10 OD018521 / OD / NIH HHS / United States P50 HD103538 / HD / NICHD NIH HHS / United States |
Insights into genetics, human biology and disease gleaned from family based genomic studies.
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