SIDs Results From Genetic Heart Disease Less Than Previously Thought

The vast majority of sudden infant death syndrome (SIDS) cases are not the result of genetic heart diseases (GHDs) or a single genetic cause, according to a study published March 12 in the Journal of the American Academy of Cardiology. The researchers found that less than 5 percent of infants who died from SIDS possess genetic variants that are immediately actionable for other family members or would lead to cascade testing.

Despite the fact that up to 80 percent of all sudden unexpected infant deaths are attributed to SIDS, pathogenic understanding of SIDS remains elusive.

In the current study, researchers conducted a whole exome molecular autopsy and targeted analysis of 90 GHD-susceptibility genes in 419 unrelated SIDS cases (257 male; average age 2.7 months) from both the United Kingdom and the United States. Additionally, case-control analysis included 973 control exomes (509 female, 464 male) from the ICR1000 U.K. exome study and the 1958 Birth Cohort study.

The 90 GHD genes included those known to be associated with susceptibility to cardiac channelopathy and cardiomyopathy. “Potentially informative” variants were defined as ultra-rare (minor allele frequency <0.00005) and located in GHD genes.

Overall, 53 of 419 SIDS cases (12.6 percent) had at least one “potentially informative,” GHD-associated variant. Less than 1 percent of cases (n = 4) had two “potentially informative” variants. According to the American College of Medical Genetics guidelines, only 4.1 percent of SIDs cases (n = 17) possessed a “pathogenic” or “likely pathogenic” variant. Additionally,

• there was no significant difference in yield between cases and controls for any specific gene.

• infants older than 4 months (past the peak age of SIDs) were more likely to host a “potentially informative” GHD-associated variant.

• there no significant associations between yield of “potentially informative” GHD gene variants and sex, sleep position, or bed sharing habits.

The researchers also compared the previously detected ultra-rare, “pathogenic” or “likely pathogenic” variants seen within sudden death– susceptibility genes among a different cohort of 302 autopsy-negative cases of sudden arrhythmic death syndrome in persons who died at an age greater than 1 year (median age 24 years) to the variants detected in this cohort. The yield was significantly lower in the SIDs cohort compared to the older sudden death cohort (4.3 percent versus 13.0 percent), leading the researchers to conclude most SIDS cases are “largely different genetically and mechanistically” from sudden death occurring after 1 year of age.

“Unfortunately, despite their rarity, most of these ultra-rare variants still remain variants of uncertain significance stuck in genetic purgatory,” write the authors led by David Tester, from the Mayo Clinic in Rochester, Minn. “Importantly, not all of these variants have been characterized functionally, and great caution must still be exercised, even when interpreting ultra-rare variants residing within the major channelopathy genes… Overattribution of SIDS deaths to GHDs has significant implications for the immediate family, and we urge extreme caution in variant interpretation.”

Takeaway: Previous research may have overly attributed GHD-related variants as a causative factor in SIDS pathology.