Cardiac Genetic Predisposition in Sudden Infant Death Syndrome

• Published in: Journal of the American College of Cardiology Vol. 71; no. 11; pp. 1217 - 1227
• Main Authors: Tester, David J., Wong, Leonie C.H., Chanana, Pritha, Jaye, Amie, Evans, Jared M., FitzPatrick, David R., Evans, Margaret J., Fleming, Peter, Jeffrey, Iona, Cohen, Marta C., Tfelt-Hansen, Jacob, Simpson, Michael A., Behr, Elijah R., Ackerman, Michael J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.03.2018; Elsevier Limited
• Subjects: Age; Cardiology; Cardiomyopathy; Cardiovascular; Channelopathy; Coronary artery disease; Deoxyribonucleic acid; DNA; Ethnicity; Europe - epidemiology; Exome Sequencing - methods; Exome Sequencing - statistics & numerical data; Female; Gene Frequency; genetic heart diseases; Genetic Predisposition to Disease - epidemiology; Genetic testing; Genetic Testing - methods; Genetic Variation; Genomes; Genomics; Heart diseases; Humans; Hypotheses; Infant; Infant mortality; Infant, Newborn; Infants; KCNQ1 protein; Long QT syndrome; Male; Medical examiners; Minority & ethnic groups; molecular autopsy; Mutation; Needs Assessment; Polymerase chain reaction; Population; Potassium channels (voltage-gated); SIDS; Sudden Infant Death - epidemiology; Sudden Infant Death - genetics; Sudden infant death syndrome; whole exome sequencing; Europe; California; United Kingdom > UK; United States > US; Massachusetts; NSV; GHD; MAF; SIDS; genetic heart diseases; WES; LQTS; sudden infant death syndrome; gnomAD; whole exome sequencing; molecular autopsy; PCA; long QT syndrome; genetic heart disease; Genome Aggregation Database; nonsynonymous variant; minor allele frequency; principal component analysis
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2018.01.030

Sudden infant death syndrome (SIDS) is a leading cause of postneonatal mortality. Genetic heart diseases (GHDs) underlie some cases of SIDS. This study aimed to determine the spectrum and prevalence of GHD-associated mutations as a potential monogenic basis for SIDS. 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. 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. 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. [Display omitted]