title: A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y.
abstract: Thousands die each year from sudden infant death syndrome (SIDS). Neither the cause nor basis for varied prevalence in different populations is understood. While 2 cases have been associated with mutations in type Valpha, cardiac voltage-gated sodium channels (SCN5A), the "Back to Sleep" campaign has decreased SIDS prevalence, consistent with a role for environmental influences in disease pathogenesis. Here we studied SCN5A in African Americans. Three of 133 SIDS cases were homozygous for the variant S1103Y. Among controls, 120 of 1,056 were carriers of the heterozygous genotype, which was previously associated with increased risk for arrhythmia in adults. This suggests that infants with 2 copies of S1103Y have a 24-fold increased risk for SIDS. Variant Y1103 channels were found to operate normally under baseline conditions in vitro. As risk factors for SIDS include apnea and respiratory acidosis, Y1103 and wild-type channels were subjected to lowered intracellular pH. Only Y1103 channels gained abnormal function, demonstrating late reopenings suppressible by the drug mexiletine. The variant appeared to confer susceptibility to acidosis-induced arrhythmia, a gene-environment interaction. Overall, homozygous and rare heterozygous SCN5A missense variants were found in approximately 5% of cases. If our findings are replicated, prospective genetic testing of SIDS cases and screening with counseling for at-risk families warrant consideration.
authors.affiliation: Department of Pediatrics and Institute for Molecular Pediatric Sciences, Pritzker School of Medicine, Biological Sciences Division, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Leigh D
authors.initials: LD
authors.lastname: Plant
authors.forename: Peter N
authors.initials: PN
authors.lastname: Bowers
authors.forename: Qianyong
authors.initials: Q
authors.lastname: Liu
authors.forename: Thomas
authors.initials: T
authors.lastname: Morgan
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhang
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
authors.forename: Weidong
authors.initials: W
authors.lastname: Chen
authors.forename: Rick A
authors.initials: RA
authors.lastname: Kittles
authors.forename: Steve A N
authors.initials: SA
authors.lastname: Goldstein
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000235:genetics; D016022:Case-Control Studies; D002460:Cell Line; D015331:Cohort Studies; D004777:Environment; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008801:Mexiletine / Q000494:pharmacology; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013398:Sudden Infant Death / Q000235:genetics*
chemical_list: D000889:Anti-Arrhythmia Agents; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D008801:Mexiletine