Heritable Burden of Community Sudden Death by Autopsy and Molecular Phenotyping for Precision Genotype Correlation

Zian H Tseng; James W Salazar; Julianne Wojciak; W Patrick Devine; Brielle A Kinkead; Matthew Yee; David Eik; Jean Feng; Andrew J Connolly; Ellen Moffatt

doi:10.1016/j.jacep.2024.10.027

Heritable Burden of Community Sudden Death by Autopsy and Molecular Phenotyping for Precision Genotype Correlation

JACC Clin Electrophysiol. 2024 Dec 18:S2405-500X(24)00936-8. doi: 10.1016/j.jacep.2024.10.027. Online ahead of print.

Authors

Affiliations

¹ Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of California-San Francisco, San Francisco, California, USA; Cardiovascular Genetics Center, University of California-San Francisco, San Francisco, California, USA. Electronic address: [email protected].
² Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of California-San Francisco, San Francisco, California, USA. Electronic address: https://twitter.com/JamesSalazarMD.
³ Cardiovascular Genetics Center, University of California-San Francisco, San Francisco, California, USA; Department of Medicine, University of California-San Francisco, San Francisco, California, USA.
⁴ Department of Pathology, University of California-San Francisco, San Francisco, California, USA.
⁵ Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of California-San Francisco, San Francisco, California, USA.
⁶ School of Medicine, University of California-San Francisco, San Francisco, California, USA.
⁷ Department of Epidemiology and Biostatistics, University of California-San Francisco, San Francisco, California, USA.
⁸ Office of the Chief Medical Examiner, City and County of San Francisco, San Francisco, California, USA.

PMID: 39708038
DOI: 10.1016/j.jacep.2024.10.027

Abstract

Background: Sudden cardiac death (SCD) genetic studies neglect the majority occurring in older decedents with cardiovascular pathology.

Objectives: This study sought to determine the burden of genetic disease in unselected adult sudden deaths by precision genotype-postmortem phenotype correlation.

Methods: The authors used autopsy, histology, and toxicology to adjudicate cause and identify high-suspicion phenotypes (eg, hypertrophic cardiomyopathy) among presumed SCDs aged 18 to 90 years referred to the county medical examiner from February 2011 to January 2018. They tested 231 genes associated with sudden death and correlated genotype with postmortem phenotypes, including myocardial analysis. Family history in high-suspicion phenotype cases was obtained.

Results: Of 856 autopsied presumed SCDs, families of 359 consented and 306 cases (66% cardiac cause) ultimately underwent genetic testing (mean age 62 years, 74% male). Seventy-five cases met high-suspicion phenotype criteria (8.8%), of which 36 underwent testing; 18 families met with a genetic counselor. We found 14 cases with autosomal dominant or X-linked pathogenic/likely pathogenic (P/LP) variants (apparent yield 4.6%); 6 had concordant cause (corrected yield 2%). Yields restricted to autopsy-confirmed cardiac causes (2.5%) and high-suspicion phenotypes (2.7%) were similar. Myocardial genotyping in 14 high-suspicion decedents matched negative blood genotyping, thus did not support somatic mosaicism. Myocardial RNA in a P/LP PKP2 carrier without phenotype demonstrated nonsense-mediated escape as potential mechanism for incomplete penetrance. One-half of high-suspicion cases had a family history of a related condition or sudden death.

Conclusions: In this 7-year countywide study, 2% of total sudden deaths and 2.5% of confirmed SCDs had identifiable genetic cause, corrected for genotype-phenotype concordance. These results do not support routine genetic testing for community sudden deaths, particularly without autopsy.

Keywords: autopsy; genetics; sudden cardiac death.