Variant Frequency and Clinical Phenotype Call Into Question the Nature of Minor, Nonsyndromic Long-QT Syndrome-Susceptibility Gene-Disease Associations.

Keywords: genetics; genotype; long QT syndrome; penetrance; phenotype EN genetics genotype long QT syndrome penetrance phenotype 495 497 3 04/20/20 20200211 NES 200211 Long-QT syndrome (LQTS) is a 1:2500 genetic disorder characterized clinically by heart rate-corrected QT interval (QTc) prolongation and risk of torsadogenic syncope/seizures and sudden death.[1] Although 75% of LQTS cases stem from disease-causative variants in the 3 canonical LQTS-susceptibility genes ( I KCNQ1 i , I KCNH2 i , and I SCN5A i ), 5% to 10% of cases are attributed to 14 minor LQTS-susceptibility genes.[1] However, many of these minor LQTS-susceptibility genes were discovered before the burden of rare, and presumably innocuous, amino acid-altering genetic variation was illuminated by large-scale sequencing studies.[2] Therefore, we sought to couple the Genome Aggregation Database (gnomAD),[3] a harmonized database of >140 000 exomes/genomes derived in part from population-based sequencing projects, with phenotypic insights gleaned from a large LQTS registry to reassess the strength of minor LQTS gene-disease associations (GDAs). Two functional KCNE2 variants (p.Thr10Met-KCNE2 and p.Met54Thr-KCNE2) deemed previously to cause KCNE2-LQTS were observed in LQTS patients, but only in those who also possessed a disease-causative variant in a canonical LQTS-susceptibility gene. [Extracted from the article]