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.
BACKGROUND
Mutations in five cardiac voltage-gated ion channel genes, including KCNQ1, HERG, SCN5A, KCNE1 and KCNE2, constitute the principal cause of inherited long-QT syndrome (LQTS). Typically, each family carries its own private mutation, and the disease manifests with varying phenotype and incomplete penetrance, even within particular families. We had previously identified 14 different LOTS-causing mutations in 92 Finnish families.


OBJECTIVE
In order to complete the characterization of Finnish spectrum of LOTS genes, we conducted a systematic search for mutations in the five LOTS genes among 188 additional unrelated probands.


METHODS
The screening was performed by denaturing high-performance liquid chromatography (dHPLC) and DNA sequencing.


RESULTS
Nineteen novel and 12 previously described mutations were identified. Collectively, these data extend the number of molecularly defined affected Finnish LOTS families and patients at present to 150 and 939, respectively. Four presumable founder mutations (KCNQ1 G589D and IVS7-2A > G, HERG R176W and L552S) together account for as much as 73% of all established Finnish LQTS cases.


CONCLUSIONS
The extent of genetic homogeneity underlying LOTS in Finland is unique in the whole world, providing a major advantage for screening and presymptomatic diagnosis of LOTS, and constituting an excellent basis to study the role of genetic and non-genetic factors influencing phenotypic variability in this disease.
Fodstad
Heidi
H
Research Program in Molecular Medicine, Biomedicum Helsinki, Finland.
Swan
Heikki
H
Laitinen
Päivi
P
Piippo
Kirsi
K
Paavonen
Kristian
K
Viitasalo
Matti
M
Toivonen
Lauri
L
Kontula
Kimmo
K
D027682:Cation Transport Proteins / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D005387:Finland; D018703:Founder Effect; D005820:Genetic Testing; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D011110:Polymorphism, Genetic; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D015222:Sodium Channels / Q000235:genetics
D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; D015222:Sodium Channels; C059983:potassium channel protein I(sk)