title: Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results.
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.
authors.affiliation: Treuman Katz Center for Pediatric Bioethics, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Holly K
authors.initials: HK
authors.lastname: Tabor
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Auer
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Seema M
authors.initials: SM
authors.lastname: Jamal
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jessica X
authors.initials: JX
authors.lastname: Chong
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Joon-Ho
authors.initials: JH
authors.lastname: Yu
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Gordon
authors.affiliation: Department of Medicine, Harvard University, Boston, MA 02114, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Graubert
authors.affiliation: Cardiovascular Epidemiology and Human Genomics Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.affiliation: Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: mbamshad@u.washington.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000483:Alleles; D001483:Base Sequence; D002874:Chromosome Mapping; D059472:Exome / Q000235:genetics*; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D008957:Models, Genetic; D020412:Multifactorial Inheritance; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics*
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