Actionable, pathogenic incidental findings in 1,000 participants' exomes.
The incorporation of genomics into medicine is stimulating interest on the return of incidental findings (IFs) from exome and genome sequencing. However, no large-scale study has yet estimated the number of expected actionable findings per individual; therefore, we classified actionable pathogenic single-nucleotide variants in 500 European- and 500 African-descent participants randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. The 1,000 individuals were screened for variants in 114 genes selected by an expert panel for their association with medically actionable genetic conditions possibly undiagnosed in adults. Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants' pathogenicity was reviewed. Of the identified IFs, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Furthermore, one pathogenic and four likely pathogenic variants not listed as disease causing in HGMD were identified. These data can provide an estimate of the frequency (∼3.4% for European descent and ∼1.2% for African descent) of the high-penetrance actionable pathogenic or likely pathogenic variants in adults. The 23 participants with pathogenic or likely pathogenic variants were disproportionately of European (17) versus African (6) descent. The process of classifying these variants underscores the need for a more comprehensive and diverse centralized resource to provide curated information on pathogenicity for clinical use to minimize health disparities in genomic medicine.
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
Michael O
MO
Dorschner
Laura M
LM
Amendola
Emily H
EH
Turner
Peggy D
PD
Robertson
Brian H
BH
Shirts
Carlos J
CJ
Gallego
Robin L
RL
Bennett
Kelly L
KL
Jones
Mari J
MJ
Tokita
James T
JT
Bennett
Jerry H
JH
Kim
Elisabeth A
EA
Rosenthal
Daniel S
DS
Kim
Holly K
HK
Tabor
Michael J
MJ
Bamshad
Arno G
AG
Motulsky
C Ronald
CR
Scott
Colin C
CC
Pritchard
Tom
T
Walsh
Wylie
W
Burke
Wendy H
WH
Raskind
Peter
P
Byers
Fuki M
FM
Hisama
Deborah A
DA
Nickerson
Gail P
GP
Jarvik
D030541:Databases, Genetic; D004194:Disease / Q000235:genetics*; D059472:Exome; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D033162:Incidental Findings; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide