A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy

© 2018, American College of Medical Genetics and Genomics. Purpose: We evaluated strategies for identifying disease-causing variants in genetic testing for dilated cardiomyopathy (DCM). Methods: Cardiomyopathy gene panel testing was performed in 532 DCM patients and 527 healthy control subjects. Rare variants in 41 genes were stratified using variant-level and gene-level characteristics. Results: A majority of DCM cases and controls carried rare protein-altering cardiomyopathy gene variants. Variant-level characteristics alone had limited discriminative value. Differentiation between groups was substantially improved by addition of gene-level information that incorporated ranking of genes based on literature evidence for disease association. The odds of DCM were increased to nearly 9-fold for truncating variants or high-impact missense variants in the subset of 14 genes that had the strongest biological links to DCM (P