Large numbers of genetic variants considered to be pathogenic are common in asymptomatic individuals.

Hum Mutat
Authors
Keywords
Abstract

It is now affordable to order clinically interpreted whole-genome sequence reports from clinical laboratories. One major component of these reports is derived from the knowledge base of previously identified pathogenic variants, including research articles, locus-specific, and other databases. While over 150,000 such pathogenic variants have been identified, many of these were originally discovered in small cohort studies of affected individuals, so their applicability to asymptomatic populations is unclear. We analyzed the prevalence of a large set of pathogenic variants from the medical and scientific literature in a large set of asymptomatic individuals (N = 1,092) and found 8.5% of these pathogenic variants in at least one individual. In the average individual in the 1000 Genomes Project, previously identified pathogenic variants occur on average 294 times (σ = 25.5) in homozygous form and 942 times (σ = 68.2) in heterozygous form. We also find that many of these pathogenic variants are frequently occurring: there are 3,744 variants with minor allele frequency (MAF) ≥ 0.01 (4.6%) and 2,837 variants with MAF ≥ 0.05 (3.5%). This indicates that many of these variants may be erroneous findings or have lower penetrance than previously expected.

Year of Publication
2013
Journal
Hum Mutat
Volume
34
Issue
9
Pages
1216-20
Date Published
2013 Sep
ISSN
1098-1004
URL
DOI
10.1002/humu.22375
PubMed ID
23818451
PubMed Central ID
PMC3786140
Links
Grant list
R01 GM078598 / GM / NIGMS NIH HHS / United States
GM078598 / GM / NIGMS NIH HHS / United States
K99 HG007229 / HG / NHGRI NIH HHS / United States
R00 HG007229 / HG / NHGRI NIH HHS / United States
HG007229 / HG / NHGRI NIH HHS / United States