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

Abstract

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 > or =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=9.0x10(-13)). The KCNH2 R176W variant (n=16) resulted in a 22 ms (SE 4.7) longer adjusted QT interval (P=2.1x10(-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.

Figure 1

The QTc intervals in founder mutation non-carriers (A) (n=4758) and carriers (B) (n=25) (P=1.26×10^-9), after exclusion of cases with potentially QTc-altering traits or medications. The boxes represent the median values (bolded horizontal lines) and the 25th to 75th percentiles of the mean QTc intervals. The fine lines refer to the highest and lowest values that are not outliers. Circles represent values >1.5-fold the interquartile range, and asterisks refer to values >3-fold the range indicated by the box.