Molecular autopsy in unexplained sudden death: a systematic review and meta-analysis of ACMG-corrected diagnostic yield, genomic architecture, and family translation.
Raghvendra Singh, Ravindra Kumar Garg, Heena Singh et al.
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In 30 seconds
This PRISMA-based systematic review and random-effects meta-analysis assessed postmortem genetic testing in unexplained sudden death. The quantitative synthesis included 4,041 index cases from 44 studies; 35 studies reported family-translation data. The pooled ACMG-corrected diagnostic yield was approximately 13%, with substantial heterogeneity. Broader sequencing approaches had modestly higher yield than candidate or restricted panels (OR 1.36, 95% CI 1.09-1.70; p = 0.006), alongside greater VUS burden. The review also found age-related differences in yield and genomic architecture, and described family screening and risk stratification as important downstream applications.
Key findings
- Pooled ACMG-corrected diagnostic yield was approximately 13%, with substantial heterogeneity across studies.
- Broader sequencing approaches had higher yield than candidate/restricted panels (OR 1.36, 95% CI 1.09-1.70; p = 0.006), but greater VUS burden.
- Young adult/adult cohorts had the highest pooled yield; infant/pediatric cohorts showed broader multisystem genomic architecture and higher VUS burden.
- Family-translation data from 35 studies frequently reported genotype-positive and phenotype-positive relatives, segregation analysis, and clinically actionable interventions.
Why it matters
The findings indicate that molecular autopsy can identify a genetic explanation in a meaningful minority of unexplained sudden deaths, while also generating uncertain variants that require careful interpretation. Its potential value extends to relatives: combining genetic results with phenotype assessment and segregation may support family risk evaluation and preventive care, although the review reports heterogeneous evidence across cohorts and sequencing approaches.
What to keep in mind
The pooled yield showed substantial heterogeneity, and broader sequencing was associated with greater VUS burden. Family-translation data came from 35 studies, including 25 overlapping index-case cohorts.