Cardiac Genetic Predisposition in Sudden Infant Death Syndrome

BACKGROUND Sudden infant death syndrome (SIDS) is a leading cause of postneonatal mortality. Genetic heart diseases (GHDs) underlie some cases of SIDS. OBJECTIVES This study aimed to determine the spectrum and prevalence of GHD-associated mutations as a potential monogenic basis for SIDS. METHODS A cohort of 419 unrelated SIDS cases (257 male; average age 2.7 +/- 1.9 months) underwent whole exome sequencing and a targeted analysis of 90 GHD-susceptibility genes. The yield of potentially informative, ultra-rare variants (minor allele frequency < 0.00005) in GHD-associated genes was assessed. RESULTS Overall, 53 of 419 (12.6%) SIDS cases had >= 1 potentially informative, GHD-associated variant. The yield was 14.9% (21 of 141) for mixed-European ancestry cases and 11.5% (32 of 278) for European ancestry SIDS cases. Infants older than 4 months were more likely to host a potentially informative GHD-associated variant. There was significant overrepresentation of ultra-rare nonsynonymous variants in European SIDS cases (18 of 278 [6.5%]) versus European control subjects (30 of 973 [3.1%]; p = 0.013) when combining all 4 major cardiac channelopathy genes (KCNQ1, KCNH2, SCN5A, and RYR2). According to the American College of Medical Genetics guidelines, only 18 of 419 (4.3%) SIDS cases hosted a pathogenic or likely pathogenic variant. CONCLUSIONS Less than 15% of more than 400 SIDS cases had a potentially informative variant in a GHD-susceptibility gene, predominantly in the 4-to 12-month age group. Only 4.3% of cases possessed immediately clinically actionable variants. Consistent with previous studies, ultra-rare, nonsynonymous variants within the major cardiac channelopathy-associated genes were overrepresented in SIDS cases in infants of European ethnicity. These findings have major implications for the investigation of SIDS cases and families. (c) 2018 the American College of Cardiology Foundation. Published by Elsevier. All rights reserved.