Using larger gene panels in clinical exome and genome analysis can maximize diagnostic yield in genetically heterogeneous diseases, but they will frequently prioritize benign candidate variants, highlighting the need for careful phenotypic selection of individuals for panel testing, according to a new study appearing this week in Genetics in Medicine. Gene panels can vary significantly in size, and although studies suggest that bigger is not always better, a focus on maximizing diagnostic yield can result in a tendency toward ever larger panels. To investigate how gene panel size affects the background rate of candidate variants prioritized for classification, a pair of scientists from the University of Exeter used exome sequencing data from more than 200,000 people in the UK Biobank — which is known to have a strong ascertainment bias toward healthy adults — to test five clinically curated gene panels that were developed to diagnose a range of heterogeneous monogenic diseases. The researchers find that for every 100 genes in a gene panel, approximately .2 rare predicted loss of function and missense variants prioritized in each individual, increasing linearly with the number of genes in the panel. "This finding suggests that for larger gene panels, almost every individual tested will have at least one rare nonsynonymous candidate diagnostic variant that is likely to be benign," they write. "Overall, we suggest that extreme caution should be applied when interpreting candidate pathogenic variants from large gene panel analyses, particularly in the absence of relevant phenotypes."
Study Highlights Pitfall of Large Gene Panels in Clinical Genomic Analysis
Aug 05, 2022