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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population
Circulation, Volume 112, No. 17, Year 2005
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Description
Background - In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately AD 1700 and segregating the same KCNQ1 mutation (A341V). Methods and Results - The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking β-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (≤440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate <73 bpm were at significantly lower risk (OR=0.23; 95% CI, 0.06 to 0.86; P=0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7±4 versus 13±9 years, both P<0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IKs were conducted and identified a dominant negative effect of the mutation on wild-type channels. Conclusions - KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor. © 2005 American Heart Association, Inc.
Authors & Co-Authors
Brink, Paul A.
South Africa, Stellenbosch
Stellenbosch University
CROTTI, L.
Italy, Pavia
Università Degli Studi Di Pavia
Italy, Pavia
Fondazione Irccs Policlinico San Matteo
Corfield, Valérie Ann
South Africa, Stellenbosch
Stellenbosch University
Goosen, Althea
South Africa, Stellenbosch
Stellenbosch University
Durrheim, Glenda A.
South Africa, Stellenbosch
Stellenbosch University
Hedley, P. L.
South Africa, Stellenbosch
Stellenbosch University
Heradien, Marshall J.
South Africa, Stellenbosch
Stellenbosch University
Geldenhuys, G.
South Africa, Stellenbosch
Stellenbosch University
Vanoli, Emilio
Italy, Pavia
Università Degli Studi Di Pavia
Bacchini, Sara
Italy, Pavia
Università Degli Studi Di Pavia
Spazzolini, Carla
Italy, Pavia
Università Degli Studi Di Pavia
Lundquist, Andrew L.
United States, Nashville
Vanderbilt University
Roden, Dan M.L.
United States, Nashville
Vanderbilt University
George, Alfred L.
United States, Nashville
Vanderbilt University
Schwartz, Peter J.
South Africa, Stellenbosch
Stellenbosch University
Italy, Pavia
Università Degli Studi Di Pavia
Italy, Pavia
Fondazione Irccs Policlinico San Matteo
Statistics
Citations: 15
Authors: 15
Affiliations: 4
Identifiers
Doi:
10.1161/CIRCULATIONAHA.105.572453
ISSN:
00097322
Research Areas
Cancer
Genetics And Genomics
Noncommunicable Diseases
Study Design
Cross Sectional Study
Study Locations
South Africa