Estimating the Posttest Probability of Long QT Syndrome Diagnosis for Rare KCNH2 Variants

Large-scale phenotyping efforts in largely healthy populations, coupled with DNA sequencing, suggest variants currently annotated as pathogenic are more common in healthy populations than previously thought. In addition, novel and rare variants are frequently observed in genes associated with disease both in healthy individuals and those under suspicion of disease. We assessed the degree to which the presence of a variant in the cardiac potassium channel gene KCNH2 was diagnostically predictive for the autosomal dominant. We show how variant-specific features can inform a prior probability of disease for rare variants even in the absence of clinically phenotyped heterozygotes. long QT syndrome.