Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome

Michael J. Ackerman, Benjamin L. Siu, William Q. Sturner, David J. Tester, Carmen R. Valdivia, Jonathan C. Makielski, Jeffrey A. Towbin

Research output: Contribution to journalArticlepeer-review

389 Scopus citations


Context Fatal arrhythmias from occult long QT syndrome may be responsible for some cases of sudden infant death syndrome (SIDS). Because patients who have long QT syndrome with sodium channel gene (SCNSA) defects have an increased frequency of cardiac events during sleep, and a recent case is reported of a sporadic SCN5A mutation in an infant with near SIDS, SCN5A has emerged as the leading candidate ion channel gene for SIDS. Objective To determine the prevalence and functional properties of SCN5A mutations in SIDS. Design, Setting, and Subjects Postmortem molecular analysis of 93 cases of SIDS or undetermined infant death identified by the Medical Examiner's Office of the Arkansas State Crime Laboratory between September 1997 and August 1999. Genomic DNA was extracted from frozen myocardium and subjected to SCN5A mutational analyses. Missense mutations were incorporated into the human heart sodium channel α subunit by mutagenesis, transiently transfected into human embryonic kidney cells, and characterized electrophysiologically. Main Outcome Measures Molecular and functional characterization of SCN5A defects. Results Two of the 93 cases of SIDS possessed SCN5A mutations: a 6-week-old white male with an A997S missense mutation in exon 17 and a 1-month old white male with an R1826H mutation in exon 28. These 2 distinct mutations occurred in highly conserved regions of the sodium channel and were absent in 400 control patients (800 alleles). Functionally, the A997S and R1826H mutant channels expressed a sodium current characterized by slower decay and a 2- to 3-fold increase in late sodium current. Conclusion Approximately 2% of this prospective, population-based cohort of SIDS cases had an identifiable SCN5A channel defect, suggesting that mutations in cardiac ion channels may provide a lethal arrhythmogenic substrate in some infants at risk for SIDS.

Original languageEnglish (US)
Pages (from-to)2264-2269
Number of pages6
Issue number18
StatePublished - Nov 14 2001

ASJC Scopus subject areas

  • General Medicine


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