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Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results.

TitlePathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results.
Publication TypeJournal Article
Year of Publication2014
AuthorsTabor HK, Auer PL, Jamal SM, Chong JX, Yu J-H, Gordon AS, Graubert TA, O'Donnell CJ, Rich SS, Nickerson DA
Secondary AuthorsBamshad MJ
Corporate AuthorsNHLBI Exome Sequencing Project
JournalAm J Hum Genet
Volume95
Issue2
Pagination183-93
Date Published2014 Aug 07
ISSN1537-6605
KeywordsAfrican Americans, Alleles, Base Sequence, Chromosome Mapping, European Continental Ancestry Group, Exome, Genetic Variation, Genome, Human, Humans, Macular Degeneration, Models, Genetic, Multifactorial Inheritance, Sequence Analysis, DNA
Abstract

Exome sequencing (ES) is rapidly being deployed for use in clinical settings despite limited empirical data about the number and types of incidental results (with potential clinical utility) that could be offered for return to an individual. We analyzed deidentified ES data from 6,517 participants (2,204 African Americans and 4,313 European Americans) from the National Heart, Lung, and Blood Institute Exome Sequencing Project. We characterized the frequencies of pathogenic alleles in genes underlying Mendelian conditions commonly assessed by newborn-screening (NBS, n = 39) programs, genes associated with age-related macular degeneration (ARMD, n = 17), and genes known to influence drug response (PGx, n = 14). From these 70 genes, we identified 10,789 variants and curated them by manual review of OMIM, HGMD, locus-specific databases, or primary literature to a total of 399 validated pathogenic variants. The mean number of risk alleles per individual was 15.3. Every individual had at least five known PGx alleles, 99% of individuals had at least one ARMD risk allele, and 45% of individuals were carriers for at least one pathogenic NBS allele. The carrier burden for severe recessive childhood disorders was 0.57. Our results demonstrate that risk alleles of potential clinical utility for both Mendelian and complex traits are detectable in every individual. These findings highlight the necessity of developing guidelines and policies that consider the return of results to all individuals and underscore the need to develop innovative approaches and tools that enable individuals to exercise their choice about the return of incidental results.

DOI10.1016/j.ajhg.2014.07.006
Alternate JournalAm J Hum Genet
PubMed ID25087612
PubMed Central IDPMC4129409
Grant ListRC2 HL102923 / HL / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
RC2 HL-102926 / HL / NHLBI NIH HHS / United States
RC2 HL-102923 / HL / NHLBI NIH HHS / United States
T32 HL007208 / HL / NHLBI NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
P20 MD006899 / MD / NIMHD NIH HHS / United States
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States