Cardiac Genetic Predisposition in Sudden Infant Death Syndrome

David J Tester, Leonie C H Wong, Pritha Chanana, Amie Jaye, Jared M Evans, David R FitzPatrick, Margaret J Evans, Peter Fleming, Iona Jeffrey, Marta C Cohen, Jacob Tfelt-Hansen, Michael A Simpson, Elijah R Behr, Michael J Ackerman

    Abstract

    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.

    OriginalsprogEngelsk
    TidsskriftJournal of the American College of Cardiology
    Vol/bind71
    Udgave nummer11
    Sider (fra-til)1217-1227
    Antal sider11
    ISSN0735-1097
    DOI
    StatusUdgivet - 20 mar. 2018

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