A founder mutation of the potassium channel KCNQ1 in long QT syndrome - Implications for estimation of disease prevalence and molecular diagnostics

OBJECTIVES We took advantage of the genetic isolate of Finns to characteriz e a common long QT syndrome (LQTS) mutation, and to estimate the prevalence of LOTS. BACKGROUND The LOTS is caused by mutations in different ion channel genes, which vary ic their molecular nature from family to family. METHODS The potassium channel gene KCNQ1 was sequenced in two unrelated Fin nish patients with Jervell and Lange-Nielsen syndrome (JLNS), followed by g enotyping of 114 LQTS probands and their available family members. The func tional properties of the mutation were studied using a whole-sell patch-cla mp technique. RESULTS We identified a novel missense mutation (G589D or KCNQ1-Fin) in the C-terminus of the KCNQ1 subunit. The voltage threshold of activation for t he KCNQ1-Fin channel Tvas markedly increased compared to the wild-type chan nel. This mutation was present in homozygous form in two siblings with JLNS , and in heterozygous form in 34 of 114 probands with Romano-Ward syndrome (RWS) and 282 family members. The mean (+/- SD) rate-corrected QT intervals of the heterozygous subjects (n = 316) and noncarriers (n = 423) were 460 +/- 40 ms and 410 +/- 20 ms (p < 0.001), respectively. CONCLUSIONS A single missense mutation of the KCNQ1 gene accounts for 30% o f Finnish cases with LQTS, and it may be associated with both the RWS and J LNS phenotypes of the syndrome. The relative enrichment of this mutation mo st likely represents a founder gene effect. These circumstances provide ail excellent opportunity to examine how genetic and nongeneric factors modify the LOTS phenotype. (C) 2001 by the American College of Cardiology.