Assessment of incidental findings in 232 whole-exome sequences from the Baylor–Hopkins Center for Mendelian Genomics

Abstract

PurposeIn March 2013, the ACMG published a list of 56 genes with the recommendation that pathogenic and likely pathogenic variants detected incidentally by clinical sequencing should be reported to patients. As an initial step in determining the practical consequences of this recommendation in the research setting, we searched for variants in these genes in 232 whole exome sequences from the Baylor-Hopkins Center for Mendelian Genomics.MethodsWe identified rare, nonsynonymous and splicing SNVs and indels and assessed variant classification using HGMD, Emory and ClinVar databases. We analyzed the burden of mutation in each of the 56 genes and determined which variants should be reported to patients.ResultsOur filtering resulted in 249 distinct variants, with a mean of 1.69 variants per individual. Half of these were novel missense mutations not classified by any of the 3 reference databases. Of 101 variants listed in HGMD, 48 were also in ClinVar and 3 were also in Emory; half of these shared variants were classified discordantly between databases. Some genes consistently had greater variation than others. In total, 0.86% of individuals had a reportable incidental variant.ConclusionThese observations demonstrate some current challenges of assessing phenotypic consequences of incidental variants for counseling patients.

Aggregate penetrance of genomic variants for actionable disorders in European and African Americans

“…The frequencies we found for PVs and LPVs in the FHS and JHS populations are similar to recent assessments of PVs in medically actionable genes among large collections of individuals with exome sequences (29, 30) and to others who have reported variants in the ACMG56 among collections of exomes or genomes (31, 32). As in these reports, most of the PVs described here are predicted to encode null alleles and result in haploinsufficiency, a well-defined mechanism of pathogenicity for most genetic diseases.…”

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

“…Since the ACMG released their recommendations, several groups have tried to estimate frequencies of actionable variants in 56 genes for diverse samples and by using different methods [10][11][12][13][14][15]. Using WGS or WES data, some studies [15,16] tried to estimate the frequencies of pathogenic variants in the recommended genes for European and African ancestries, and target populations of the 1000 Genomes Project.…”

Ethics and Empiricism in the Formation of Professional Guidelines

“…For example, we already know something about how often "incidental" findings from genome sequencing might occur, and it is probably more often than was thought when the two sets of recommendations were drafted. (Yang et al 2013;Jurgens et al 2013) Furthermore, many of the people who participated in drafting the recommendations were themselves conducting empirical research on the effects of clinical sequencing. Yet, positions were taken in the absence of considering these data.…”