Yield of Postmortem Genetic Testing in Sudden Arrhythmic Death Syndrome: A Systematic Review and Meta-Analysis

Sudden arrhythmic death syndrome (SADS) refers to sudden cardiac death with structurally normal hearts at autopsy, most frequently attributed to inherited arrhythmia syndromes or concealed cardiomyopathies. Postmortem genetic testing may help identify underlying genetic causes. We aimed to investigate the yield of postmortem genetic testing in SADS cases by determining the prevalence of pathogenic or likely pathogenic variants in channelopathy- and cardiomyopathy-associated genes in autopsy-negative SADS victims.

This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered in PROSPERO (REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD420251067244). PubMed and Embase were searched on June 4, 2025, for observational studies including individuals aged 1 to 50 years with SADS and negative or nonspecific findings at autopsy. Eligible studies reported postmortem genetic testing for channelopathy and cardiomyopathy genes. Pathogenic or likely pathogenic variant classification followed American College of Medical Genetics and Genomics criteria and ClinGen gene-disease associations. Pooled prevalence was estimated using random-effects models.

A total of 45 studies involving 2498 SADS cases were included. Among 1697 SADS victims tested for both channelopathy and cardiomyopathy genes (33 studies), the pooled prevalence of pathogenic or likely pathogenic variants was 11.1% (95% CI, 4.1%-26.6%, I²=50.7%). Testing for cardiomyopathy genes (33 studies, 1697 cases) and for channelopathy genes (42 studies, 2354 cases) yielded a prevalence of 7.0% (95% CI, 1.9%-22.9%, I²=51.9%) and 6.3% (95% CI, 2.0%-18.4%, I²=49.8%), respectively. The most frequently involved genes encoded sarcomeric proteins and ion channels, with TTN, MYBPC3, MYH7, KCNH2, and SCN5A among the most commonly affected.

Postmortem genetic testing identifies pathogenic or likely pathogenic variants in a significant subset of SADS cases, supporting its utility in postmortem evaluation.