Phenotype-driven molecular autopsy for sudden cardiac death

A phenotype driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. 46 cases aged 1-40 years had normal hearts and suspected arrhythmic death. 7 (15%) had likely pathogenic variants in ion channelopathy genes (KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)). 50 cases aged between 2 and 67 had a cardiomyopathy. 25 had Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), 10 Dilated Cardiomyopathy (DCM) and 15 Hypertrophic Cardiomyopathy (HCM). Likely pathogenic variants were found in 3 ARVC cases (12%) in PKP2, DSC2 or DSP, 2 DCM cases (20%) in MYH7, and 4 HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In 3 families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths.