Cardiac Genetic Analyses in SIDS

Study Questions:

What percentage of sudden infant death syndrome (SIDS) deaths could be potentially attributed to an underlying genetic heart disease (GHD) based on whole exome sequencing (WES)?


The investigators conducted WES and targeted genetic analysis for known pathogenic mutations of SIDS cases in infants <1 year of age, of European descent, and with otherwise negative autopsy evaluation.


WES was analyzed in 419 cases of SIDS, which occurred at a mean age of 2.7 ± 1.9 months. In total, 285 “ultra-rare” non-synonymous variants (NSVs) were identified in 194 of the 419 SIDS cases. Of these, 20% were considered potentially significant based on location, predicted impact, and prior reports in literature. Ultimately, after strict vetting, only 17 of the 285 NSVs (4.1%) were deemed pathogenic or likely pathogenic. Case control analysis comparing this cohort to European controls showed a significantly higher occurrence of NSVs in the SIDS cases (6.5% vs 3.1%; p = 0.013).


Less than 5% of SIDS deaths can be reasonably attributed to underlying GHD despite the identification of a significantly higher percentage of identified variants, of which most do not convincingly impose a clear pathology.


Advances in genetic analysis and knowledge on GHD have led to interest in identifying genetic causes of SIDS. Prior studies have found up to a 34% incidence of potentially significant mutations. Tester and colleagues take their analysis further by strictly vetting the variants based on functional impact to determine the more likely contribution of GHD. To quote their discussion, ‘the challenge of the WES molecular autopsy does not lie in the identification of variants, but rather, in the adjudication of their potential pathogenicity.’

Keywords: Arrhythmias, Cardiac, Autopsy, Genetic Predisposition to Disease, Genetic Testing, Heart Defects, Congenital, Infant, Mutation, Pediatrics, Sudden Infant Death, Virulence

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