Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers

Abstract

Mutations in the KCNQ1, HERG, SCN5A, minK and MiRP1 genes cause long QT syndrome (LQTS), of which there are two forms: the Romano Ward syndrome and the Jervell and Lange‐Nielsen syndrome. We have performed DNA sequencing of the LQTS‐associated genes in 169 unrelated patients referred for genetic testing with respect to Romano Ward syndrome and in 13 unrelated patients referred for genetic testing with respect to Jervell and Lange‐Nielsen syndrome. A total of 37 different mutations in the 5 genes, of which 20 were novel, were identified. Among patients with the most stringent clinical criteria of Romano Ward syndrome, a mutation was identified in 71 %. Twelve of the 13 unrelated patients referred for genetic testing with respect to Jervell and Lange‐Nielsen syndrome were provided with a molecular genetic diagnosis. Cascade genetic screening of 505 relatives of index patients with molecularly defined LQTS identified 251 mutation carriers. The observed penetrance was 41 %. Although caution must be exerted, the prevalence of heterozygotes for mutations in the LQTS‐associated genes in Norway could be in the range 1/100–1/300, based on the prevalence of patients with Jervell and Lange‐Nielsen syndrome.