A KCNQ1 V205M missense mutation causes a high rate of long QT syndrome in a First Nations community of northern British Columbia: a community-based approach to understanding the impact

Genet Med. 2008 Jul;10(7):545-50. doi: 10.1097/gim.0b013e31817c6b19.


Purpose: Hereditary long QT syndrome is named for a prolonged QT interval reflecting predisposition to ventricular arrhythmias and sudden death. A high rate in a remote, northern Canadian First Nations community was brought to attention.

Methods: Two severely affected index cases and 122 relatives were ascertained using community-based participatory research principles. Genetic sequencing of five known genes responsible for long QT syndrome was carried out on the index cases, leading to the identification of a novel missense mutation. Functional properties of the identified mutation were studied in transfected mouse ltk- cells using whole cell patch clamp techniques. Corrected QT interval measurements were obtained from participants and subsequent genotyping of relatives was carried out.

Results: In the two index cases, a novel missense mutation (V205M) was identified in the S3 transmembrane helix of KvLQT1, the pore forming domain of the IKs channel complex. In transfected mouse ltk-cells the V205M mutation suppressed IKs by causing a dramatic depolarizing shift in activation voltage coupled with acceleration of channel deactivation. Twenty-two mutation carriers had a significantly higher mean corrected QT interval than noncarriers (465 +/- 28 milliseconds vs. 434 +/- 26 milliseconds, P < 0.0001); however, 30% of carriers had a corrected QT interval below 440 milliseconds.

Conclusion: A novel KCNQ1 mutation in this founder population likely confers increased susceptibility to arrhythmias because of decreased IKs current. Even with a common mutation within a relatively homogenous population, clinical expression remains variable, exemplifying the multifactorial nature of long QT syndrome, and supporting the difficulty of definitive diagnosis without genetic testing. A community participatory approach enabled a comprehensive evaluation of the impact.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • British Columbia / epidemiology
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Indians, North American / ethnology
  • Indians, North American / genetics*
  • KCNQ1 Potassium Channel / genetics*
  • KCNQ1 Potassium Channel / metabolism
  • Long QT Syndrome / epidemiology*
  • Long QT Syndrome / ethnology
  • Long QT Syndrome / genetics*
  • Mice
  • Mutation, Missense / genetics*
  • Patch-Clamp Techniques
  • Pedigree
  • Sequence Analysis, DNA


  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human