Abstract 13448: The Cardiac Sodium Nav1.5 Channelsome and Sudden Infant Death Syndrome
Introduction: Nearly 3000 infants die from sudden infant death syndrome (SIDS) in the United States each year and 10% of SIDS may stem from potentially lethal cardiac channelopathies such as long QT syndrome (LQTS) and Brugada Syndrome (BrS). Recently, a sodium channel-centric view of channelopathic SIDS has emerged, implicating the Nav1.5 sodium channel alpha subunit and its interacting proteins. Here, we detail a systematic genetic and functional analysis of the Nav1.5 channelsome for pathogenic SIDS-associated mutations.
Methods: In this IRB-approved study, DNA was obtained from 292 SIDS cases (114 females, 203 white, avg age 2.9 ± 1.9 mos, range 6 hours - 12 mos). The Nav1.5 macromolecular complex (channelsome) was investigated by analyzing the genes encoding its key components including SCN5A, SCN1B-4B, CAV3, SNTA1, GPD1L, & GJA1. 65 exons were analyzed using PCR, DHPLC, and direct DNA sequencing. Putative SIDS-associated mutations were characterized functionally via heterologous expression and whole cell or dual whole cell patch clamp.
Results: Overall, 26 SIDS victims (8.9%) harbored at least one of 24 unique, rare missense mutations: SCN5A (7), SCN3B (2), SCN4B (1), CAV3 (4), SNTA1 (6), GPD1L (2) and GJA1 (2). All missense mutations were absent in over 600 reference alleles. All 24 putative SIDS-associated mutations have been characterized functionally and 17 (71%) conferred abnormal channelopathic properties to the sodium channel macromolecular complex. Notably, 12 of these 17 cases (71%) were outside the peak age range of 2-4 months for SIDS compared to 41% for cases without a channelopathic complex (p=0.02), and 50% were over the age of 4 months (p=0.01).
Conclusions: This study demonstrates that at least 5% of SIDS may be precipitated by a specific perturbation in the heart's Nav1.5 macromolecular complex. Postmortem genetic testing of the Nav1.5 channelsome should be considered for a sudden unexplained death during infancy, particularly for those infant deaths occurring before 2 months of age or after 4 months of age. However, with nearly 30% of the rare missense mutations detected demonstrating a wild-type phenotype in vitro, assignment of mutation pathogenicity and possible SIDS causality in the absence of functional data should be avoided.
- © 2010 by American Heart Association, Inc.