Correspondence: Alfred L. George, Jr., M.D., Division of Genetic Medicine, 529 Light Hall, Vanderbilt University, Nashville TN
37232-0275, Tel: 615-936-2660; Fax: 615-936-2661,
al.george@vanderbilt.edu.
*
these authors contributed equally
DISCLOSURES: The authors have no conflicts of interest to disclose.
Clinical Summary: Congenital long-QT syndrome (LQTS) is a type of heritable primary cardiac arrhythmia susceptibility disease and
a known cause of sudden death especially in young adults and children. Among subjects found to carry the same mutation, the probability
of life-threatening cardiac events can vary considerably leading to the hypothesis that genetic factors other than the primary disease-
causing mutation may modify arrhythmic risk in LQTS. Common genetic variants in NOS1AP are associated with the QT interval duration
in the general population, and in this study, we tested whether NOS1AP variants modify the risk of clinical manifestations and the degree
of QT interval prolongation in members of a large South African LQTS population all carrying the same mutation (KCNQ1-A341V).
We found that the minor alleles of two NOS1AP variants were associated with increased risk of life-threatening events and with the
th
probability of having a rate-corrected QT interval in the upper 40 percentile (> 492 ms) of values in the study population. These
observations indicate that NOS1AP is a genetic modifier of LQTS and this knowledge should become clinically useful for risk-
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