High prevalence of four long QT syndrome founder mutations in the Finnish population

Aims. Long QT syndrome (LQTS) is an inherited arrhythmia disorder with an estimated prevalence of 0.01%–0.05%. In Finland, four founder mutations constitute up to 70% of the known genetic spectrum of LQTS. In the present survey, we sought to estimate the actual prevalence of the founder mutations and to determine their effect sizes in the general Finnish population. Methods and results. We genotyped 6334 subjects aged≥30 years from a population cohort (Health 2000 study) for the four Finnish founder mutations using Sequenom MALDI-TOF mass spectrometry. The electrocardiogram (ECG) parameters were measured from digital 12-lead ECGs, and QT intervals were adjusted for age, sex, and heart rate using linear regression. A total of 27 individuals carried one of the founder mutations resulting in their collective prevalence estimate of 0.4% (95% CI 0.3%–0.6%). The KCNQ1 G589D mutation (n=8) was associated with a 50 ms (SE 7.0) prolongation of the adjusted QT interval (P=9.0×10−13). The KCNH2 R176W variant (n=16) resulted in a 22 ms (SE 4.7) longer adjusted QT interval (P=2.1×10−6). Conclusion. In Finland 1 individual out of 250 carries a LQTS founder mutation, which is the highest documented prevalence of LQTS mutations that lead to a marked QT prolongation.

[1]  S. Priori,et al.  Genetics of cardiac arrhythmias. , 2011, Minerva medica.

[2]  A. Hofman,et al.  Common NOS1AP variants are associated with a prolonged QTc interval in the Rotterdam Study. , 2007, Circulation.

[3]  P. Schwartz,et al.  Abstract 1778: Electrocardiographic and Genetic Screening for Long QT Syndrome: Results from a Prospective Study on 44,596 Neonates , 2007 .

[4]  D. Levy,et al.  Common Genetic Variation in KCNH2 Is Associated With QT Interval Duration: The Framingham Heart Study , 2007, Circulation.

[5]  M. Nieminen,et al.  Relationship of electrocardiographic repolarization measures to echocardiographic left ventricular mass in men with hypertension , 2007, Journal of hypertension.

[6]  M. Sheppard,et al.  Arrhythmias and the athlete: mechanisms and clinical significance. , 2007, European heart journal.

[7]  L. Tiret,et al.  Confirmation of associations between ion channel gene SNPs and QTc interval duration in healthy subjects , 2007, European Journal of Human Genetics.

[8]  L. Toivonen,et al.  Further evidence of inherited long QT syndrome gene mutations in antiarrhythmic drug-associated torsades de pointes. , 2007, Heart rhythm.

[9]  H. Tan,et al.  Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system? , 2006, European heart journal.

[10]  Johnf . Thompson,et al.  Association of torsades de pointes with novel and known single nucleotide polymorphisms in long QT syndrome genes. , 2006, American heart journal.

[11]  Christian Gieger,et al.  A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization , 2006, Nature Genetics.

[12]  L. Schild,et al.  Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients , 2006, Annals of medicine.

[13]  P. Schwartz.  The congenital long QT syndromes from genotype to phenotype: clinical implications , 2006, Journal of internal medicine.

[14]  D. Roden.  Long QT syndrome: reduced repolarization reserve and the genetic link , 2006, Journal of internal medicine.

[15]  Beverley Balkau,et al.  Association of KCNQ1, KCNE1, KCNH2 and SCN5A polymorphisms with QTc interval length in a healthy population , 2005, European Journal of Human Genetics.

[16]  W. Shimizu.  The long QT syndrome: therapeutic implications of a genetic diagnosis. , 2005, Cardiovascular research.

[17]  D. Tester,et al.  Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. , 2005, Heart rhythm.

[18]  D. Levy,et al.  QT interval is a heritable quantitative trait with evidence of linkage to chromosome 3 in a genome-wide linkage analysis: The Framingham Heart Study. , 2005, Heart rhythm.

[19]  M. Viitasalo,et al.  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 , 2004, Annals of medicine.

[20]  Seppo Koskinen,et al.  HEALTH AND FUNCTIONAL CAPACITY IN FINLAND Baseline Results of the Health 2000 Health Examination Survey , 2004 .

[21]  Giuseppe Curigliano,et al.  Drug-induced prolongation of the QT interval. , 2004, The New England journal of medicine.

[22]  Michael J Ackerman,et al.  Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. , 2003, Mayo Clinic proceedings.

[23]  M. Viitasalo,et al.  A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics. , 2001, Journal of the American College of Cardiology.

[24]  A J Moss,et al.  Spectrum of Mutations in Long-QT Syndrome Genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2 , 2000, Circulation.

[25]  A. Sajantila,et al.  Homozygosity for a HERG potassium channel mutation causes a severe form of long QT syndrome: identification of an apparent founder mutation in the Finns. , 2000, Journal of the American College of Cardiology.

[26]  J. Kaprio,et al.  Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects , 2000, Human mutation.

[27]  J. Towbin,et al.  The Genetics of Cardiac Arrhythmias , 2000, Pacing and clinical electrophysiology : PACE.

[28]  S. Viskin.  Long QT syndromes and torsade de pointes , 1999, The Lancet.

[29]  L Oikarinen,et al.  Magnetocardiographic QT Interval Dispersion in Postmyocardial Infarction Patients with Sustained Ventricular Tachycardia: Validation of Automated QT Measurements , 1998, Pacing and clinical electrophysiology : PACE.

[30]  S. Priori,et al.  Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. , 1998, Circulation.

[31]  P Kligfield,et al.  Electrocardiographic detection of left ventricular hypertrophy by the simple QRS voltage-duration product. , 1992, Journal of the American College of Cardiology.

[32]  M. Leppert,et al.  The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. , 1992, The New England journal of medicine.

[33]  A. Susmano.  Effect of heart rate and autonomic tone on the QT interval. , 1982, Circulation.

[34]  M. Sokolow,et al.  The normal unipolar precordial and limb lead electrocardiogram. , 1949, American heart journal.

[35]  H. Bazett,et al.  AN ANALYSIS OF THE TIME‐RELATIONS OF ELECTROCARDIOGRAMS. , 1997 .