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(Circulation. 2007;115:361-367.)
© 2007 American Heart Association, Inc.

Pediatric Cardiology

Prevalence of Long-QT Syndrome Gene Variants in Sudden Infant Death Syndrome

Marianne Arnestad, MD^*; Lia Crotti, MD^*; Torleiv O. Rognum, MD; Roberto Insolia, BSc; Matteo Pedrazzini, BSc; Chiara Ferrandi, BSc; Ashild Vege, MD; Dao W. Wang, MD; Troy E. Rhodes, MD, PhD; Alfred L. George, Jr, MD; Peter J. Schwartz, MD

From the Institute of Forensic Medicine (M.A., T.O.R.), University of Oslo, Oslo, Norway; Molecular Cardiology Laboratory (L.C., R.I., M.P., C.F., P.J.S.), IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy; Department of Cardiology (L.C., P.J.S.), University of Pavia and IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy; Department of Laboratory Medicine (A.V.), Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; and Departments of Medicine and Pharmacology (D.W.W., T.E.R., A.L.G.), Vanderbilt University, Nashville, Tenn.

Correspondence to Dr Peter J. Schwartz, Professor & Chairman, Department of Cardiology, IRCCS Fondazione Policlinico S. Matteo, Viale Golgi 19, 27100 Pavia, Italy. E-mail pjqt{at}compuserve.com

Received August 12, 2006; accepted November 10, 2006.

Background— The hypothesis that some cases of sudden infant death syndrome (SIDS) could be caused by long-QT syndrome (LQTS) has been supported by molecular studies. However, there are inadequate data regarding the true prevalence of mutations in arrhythmia-susceptibility genes among SIDS cases. Given the importance and potential implications of these observations, we performed a study to more accurately quantify the contribution to SIDS of LQTS gene mutations and rare variants.

Methods and Results— Molecular screening of 7 genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CAV3) associated with LQTS was performed with denaturing high-performance liquid chromatography and nucleotide sequencing of genomic DNA from 201 cases diagnosed as SIDS according to the Nordic Criteria, and from 182 infant and adult controls. All SIDS and control cases originated from the same regions in Norway. Genetic analysis was blinded to diagnosis. Mutations and rare variants were found in 26 of 201 cases (12.9%). On the basis of their functional effect, however, we considered 8 mutations and 7 rare variants found in 19 of 201 cases as likely contributors to sudden death (9.5%; 95% CI, 5.8 to 14.4%).

Conclusions— We demonstrated that 9.5% of cases diagnosed as SIDS carry functionally significant genetic variants in LQTS genes. The present study demonstrates that sudden arrhythmic death is an important contributor to SIDS. As these variants likely modify ventricular repolarization and QT interval duration, our results support the debated concept that an ECG would probably identify most infants at risk for sudden death due to LQTS either in infancy or later on in life.

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