In another study, sequencing in 2022 subjects found 121 who carried rare non-synonymous variants in the congenital arrhythmia disease genes SCN5A and KCNH2.68 Three expert annotators disagreed on which ones should be called pathogenic, and review of EHRs of 48 individuals with potentially pathogenic variants identified very few arrhythmia phenotypes. These studies reinforce the ideas that penetrance is incomplete in Mendelian diseases and that current methods to determine pathogenicity need improvement. Notably, embedding sequence data in EHRs may not only enable implementation of “actionable” sequence variants, but also serves as a tool for discovering which variants are actionable: an example of the learning healthcare system.
