Molecular autopsy in unexplained sudden death: a systematic review and meta-analysis of ACMG-corrected diagnostic yield, genomic architecture, and family translation

BACKGROUND: Molecular autopsy is increasingly used in unexplained sudden death, but reported diagnostic yield varies across sequencing eras, cohort types, and variant-classification frameworks. This review evaluated ACMG-corrected diagnostic yield, genomic architecture, VUS burden, and downstream family translation. METHODS: This PRISMA-based systematic review and meta-analysis was registered in PROSPERO (CRD420251082728). Studies reporting postmortem genetic testing in sudden unexplained death were included. Quantitative diagnostic-yield synthesis included 44 core molecular autopsy studies comprising 4,041 index cases; 35 studies contributed family-translation data. Random-effects meta-analysis was performed, and subgroup analyses were conducted by sequencing strategy and age group. RESULTS: The pooled ACMG-corrected diagnostic yield was approximately 13%, with substantial heterogeneity. Broader sequencing approaches showed modestly higher yield than candidate/restricted panels (OR 1.36, 95% CI 1.09-1.70; p = 0.006), but with greater VUS burden. Young adult/adult cohorts showed the highest pooled yield, while infant/pediatric cohorts demonstrated broader multisystem genomic architecture and higher VUS burden. Recurrent substrates included RYR2, SCN5A, KCNQ1, KCNH2, TTN, and MYBPC3. Family-translation data were available from 35 studies, including 25 overlapping index-case cohorts; genotype-positive relatives, phenotype-positive relatives, segregation analysis, and clinically actionable interventions were frequently reported. CONCLUSIONS: Contemporary ACMG-compatible molecular autopsy provides modest but clinically meaningful diagnostic yield. Its major value extends beyond postmortem diagnosis, supporting family-based preventive genomic medicine through cascade screening, phenotype correlation, and targeted risk stratification.