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

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.