Four potassium channel mutations account for 73% of the genetic spectrum underlying long‐QT syndrome (LQTS) and provide evidence for a strong founder effect in Finland

Abstract

BACKGROUND. Mutations in five cardiac voltage‐gated ion channel genes, including KCNQ1, HERG, SCN5A, KCNE1 and KCNE2, constitute the principal cause of inherited long‐QT syndrome (LQTS). Typically, each family carries its own private mutation, and the disease manifests with varying phenotype and incomplete penetrance, even within particular families. We had previously identified 14 different LQTS‐causing mutations in 92 Finnish families.

AIM. In order to complete the characterization of Finnish spectrum of LQTS genes, we conducted a systematic search for mutations in the five LQTS genes among 188 additional unrelated probands.

METHODS. The screening was performed by denaturing high‐performance liquid chromatography (dHPLC) and DNA sequencing.

RESULTS. Nineteen novel and 12 previously described mutations were identified. Collectively, these data extend the number of molecularly defined affected Finnish LQTS families and patients at present to 150 and 939, respectively. Four presumable founder mutations (KCNQ1 G589D and IVS7‐2A > G, HERG R176W and L552S) together account for as much as 73% of all established Finnish LQTS cases.

CONCLUSIONS. The extent of genetic homogeneity underlying LQTS in Finland is unique in the whole world, providing a major advantage for screening and presymptomatic diagnosis of LQTS, and constituting an excellent basis to study the role of genetic and non‐genetic factors influencing phenotypic variability in this disease.

• arrhythmia
• founder gene
• ion channel
• long‐QT syndrome
• mutation