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

J Am Coll Cardiol. 2001 Feb;37(2):562-8. doi: 10.1016/s0735-1097(00)01124-4.


Objectives: We took advantage of the genetic isolate of Finns to characterize a common long QT syndrome (LQTS) mutation, and to estimate the prevalence of LQTS.

Background: The LQTS is caused by mutations in different ion channel genes, which vary in their molecular nature from family to family.

Methods: The potassium channel gene KCNQ1 was sequenced in two unrelated Finnish patients with Jervell and Lange-Nielsen syndrome (JLNS), followed by genotyping of 114 LQTS probands and their available family members. The functional properties of the mutation were studied using a whole-cell patch-damp 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 the KCNQ1-Fin channel was markedly increased compared to the wild-type channel. 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% of Finnish cases with LQTS, and it may be associated with both the RWS and JLNS phenotypes of the syndrome. The relative enrichment of this mutation most likely represents a founder gene effect. These circumstances provide an excellent opportunity to examine how genetic and nongenetic factors modify the LQTS phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • Child, Preschool
  • Deafness / genetics
  • Female
  • Finland
  • Founder Effect*
  • Gene Frequency / genetics
  • Genetics, Population
  • Genotype
  • Humans
  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • Long QT Syndrome / diagnosis
  • Long QT Syndrome / genetics*
  • Male
  • Middle Aged
  • Mutation, Missense / genetics*
  • Patch-Clamp Techniques
  • Pedigree
  • Phenotype
  • Potassium Channels / genetics*
  • Potassium Channels, Voltage-Gated*
  • Syndrome


  • KCNQ Potassium Channels
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • Potassium Channels
  • Potassium Channels, Voltage-Gated