Insights into genetics, human biology and disease gleaned from family based genomic studies.

TitleInsights into genetics, human biology and disease gleaned from family based genomic studies.
Publication TypeJournal Article
Year of Publication2019
AuthorsPosey, 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, Günel, 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 AuthorsCenters for Mendelian Genomics
JournalGenet Med
Date Published2019 04

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.

Alternate JournalGenet. Med.
PubMed ID30655598
Grant ListUM1 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
U24 HG008956 / HG / NHGRI NIH HHS / United States