Expression of a common LQT1 mutation in five apparently unrelated families in a regional inherited arrhythmia clinic.
BACKGROUND
The Inherited Arrhythmia Clinic at the University of Western Ontario services a catchment area of 1.5 million people and follows families with inherited arrhythmia syndromes.


METHODS
Patients referred for evaluation of long-QT Syndrome (LQTS) are evaluated with resting and standing ECGs, and treadmill exercise testing. Patients with findings consistent with LQTS are offered comprehensive genetic testing with screening of all first-degree relatives of genotype-positive patients.


RESULTS
Among 31 probands with disease-causing LQTS mutations, 5 probands from apparently unrelated families of Irish descent were found to have an identical disease causing transmembrane mutation in KCNQ1 (Leu266Pro). Systematic screening of 33 first-degree relatives of genotype-positive individuals detected 15 unaffected and 18 asymptomatic affected family members. Symptoms in 6 patients occurred later in life than reported LQT1 populations (61 +/- 18 years, range 44-89). In this cohort, several family members presented with cardiac arrest during acute myocardial ischemia (n = 2), sudden death, unexplained drowning, and torsade de pointes during exercise testing. There was no identifiable common relative for this cohort after pedigree construction of the previous 4-7 generations. Affected patients had mild QT prolongation at rest with dramatic QT prolongation with exercise.


CONCLUSIONS
Genetic testing in this LQTS population suggests a common KCNQ1 Leu266Pro founder effect, with the descendants clustering in our geographical region even though no common relative has been identified. The observations highlight the utility of genotypic and phenotypic correlation and a specialized clinic.
Gray
Christopher
C
Division of Cardiology, University of Western Ontario, London, Ontario, Canada.
Gula
Lorne J
LJ
Klein
George J
GJ
Skanes
Allan C
AC
Yee
Raymond
R
Sy
Raymond
R
Salisbury
Benjamin A
BA
Wong
Jorge
J
Chattha
Ishvinder
I
Subbiah
Rajesh N
RN
Krahn
Andrew D
AD
D000328:Adult; D000368:Aged; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D015994:Incidence; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009864:Ontario / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012041:Regional Medical Programs / Q000706:statistics & numerical data; D055815:Young Adult
D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human