Deleterious- and Disease-Allele Prevalence in Healthy Individuals: Insights from Current Predictions, Mutation Databases, and Population-Scale Resequencing

Abstract

We have assessed the numbers of potentially deleterious variants in the genomes of apparently healthy humans by using (1) low-coverage whole-genome sequence data from 179 individuals in the 1000 Genomes Pilot Project and (2) current predictions and databases of deleterious variants. Each individual carried 281-515 missense substitutions, 40-85 of which were homozygous, predicted to be highly damaging. They also carried 40-110 variants classified by the Human Gene Mutation Database (HGMD) as disease-causing mutations (DMs), 3-24 variants in the homozygous state, and many polymorphisms putatively associated with disease. Whereas many of these DMs are likely to represent disease-allele-annotation errors, between 0 and 8 DMs (0-1 homozygous) per individual are predicted to be highly damaging, and some of them provide information of medical relevance. These analyses emphasize the need for improved annotation of disease alleles both in mutation databases and in the primary literature; some HGMD mutation data have been recategorized on the basis of the present findings, an iterative process that is both necessary and ongoing. Our estimates of deleterious-allele numbers are likely to be subject to both overcounting and undercounting. However, our current best mean estimates of ~400 damaging variants and ~2 bona fide disease mutations per individual are likely to increase rather than decrease as sequencing studies ascertain rare variants more effectively and as additional disease alleles are discovered.

Frequency and spectrum of actionable pathogenic secondary findings in 196 Korean exomes

“…First, the frequency of secondary findings in our Korean study population falls within the range of previously published studies. 8,10,11 A prior report of 1,000 clinical exomes from European/African subjects estimated that 1.2-3.4% of its subjects had secondary findings. 8 Another study, by Xue et al, 11 of 179 healthy individuals from the 1000 Genomes Project found frequencies of up to 11%.…”

“…8,10,11 A prior report of 1,000 clinical exomes from European/African subjects estimated that 1.2-3.4% of its subjects had secondary findings. 8 Another study, by Xue et al, 11 of 179 healthy individuals from the 1000 Genomes Project found frequencies of up to 11%. A screen of 104 exomes for 448 severe recessive diseases found an average carrier burden of 2.8 variants per person.…”

Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing

“…In fact, a study involving a cohort of 1,000 individuals found that 221 unique variants observed at 566 independent instances, all of which had been classified as disease-causing in the Human Gene Mutation Database, were in fact either benign or VUS based on the evidence reported. 18 A study by Xue et al 19 found that healthy individuals carry 40-110 variants classified by the Human Gene Mutation Database as disease-causing mutations. Recent large-scale sequencing and genotyping projects have revealed a surprisingly large number of lossof-function variants-which have traditionally been viewed in the context of severe Mendelian disease-in the genomes of apparently healthy individuals.…”

Individualized Iterative Phenotyping for Genome-wide Analysis of Loss-of-Function Mutations

“…The large number of pLOF alleles is attributable to sequencing and annotation errors, gene redundancy, hypomorphic alleles, true LOF alleles for carrier states, and LOF mutations in genes that are sensitive to haploinsufficiency. 1,2 With the increasing use of next-generation sequencing technologies for predictive medicine, it is critical to be able to predict the consequences of pLOFs, especially in individuals without preexisting clinical diagnoses. Although many bioinformatic approaches have been developed to classify missense alterations, there are few tools available to assess pLOF variants.…”