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

2015; Elsevier BV; Volume: 17; Issue: 10 Linguagem: Inglês

10.1038/gim.2014.196

1530-0366

Julie A. Jurgens, Hua Ling, Kurt N. Hetrick, Elizabeth Pugh, François Schiettecatte, Kimberly F. Doheny, Ada Hamosh, Dimitri Avramopoulos, David Valle, Nara Sobreira,

Genomic variations and chromosomal abnormalities

PurposeIn March 2013 the American College of Medical Genetics and Genomics published a list of 56 genes with the recommendation that pathogenic and likely pathogenic variants detected incidentally by clinical sequencing 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 single-nucleotide variants and insertions/deletions and assessed variant classification using the Human Gene Mutation, 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 three reference databases. Of 101 variants listed in the Human Gene Mutation Database, 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.