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.
Original language | English (US) |
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Pages (from-to) | 183-193 |
Number of pages | 11 |
Journal | American journal of human genetics |
Volume | 95 |
Issue number | 2 |
DOIs | |
State | Published - Aug 7 2014 |
Funding
We acknowledge the support of the National Heart, Lung, and Blood Institute (NHLBI), the contributions of the many research institutions that participated in this study, the study investigators, field staff, and the study participants who created the Exome Sequencing Project (ESP) resource for biomedical research. Funding for the NHLBI Grand Opportunity (GO) ESP was provided by NHLBI grants RC2 HL-103010 (Heart GO), RC2 HL-102923 (Lung GO), and RC2 HL-102924 (Women’s Health Initiative Sequencing Project). Exome sequencing was supported by NHLBI grants RC2 HL-102925 (Broad GO) and RC2 HL-102926 (Seattle GO). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
ASJC Scopus subject areas
- Genetics(clinical)
- Genetics