Concealed Cardiomyopathy in Autopsy-Inconclusive Cases of Sudden Cardiac Death and Implications for Families

Julia C Isbister; Natalie Nowak; Laura Yeates; Emma S Singer; Raymond W Sy; Jodie Ingles; Hariharan Raju; Richard D Bagnall; Christopher Semsarian

doi:10.1016/j.jacc.2022.09.029

Concealed Cardiomyopathy in Autopsy-Inconclusive Cases of Sudden Cardiac Death and Implications for Families

J Am Coll Cardiol. 2022 Nov 29;80(22):2057-2068. doi: 10.1016/j.jacc.2022.09.029.

Authors

Julia C Isbister¹, Natalie Nowak², Laura Yeates³, Emma S Singer⁴, Raymond W Sy⁵, Jodie Ingles⁶, Hariharan Raju⁷, Richard D Bagnall⁴, Christopher Semsarian⁸

Affiliations

¹ Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
² Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
³ Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, New South Wales, Australia; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁴ Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
⁵ Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
⁶ Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, New South Wales, Australia; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
⁷ Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia.
⁸ Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. Electronic address: [email protected].

PMID: 36423990
DOI: 10.1016/j.jacc.2022.09.029

Abstract

Background: Genetic testing following sudden cardiac death (SCD) is currently guided by autopsy findings, despite the inherent challenges of autopsy examination and mounting evidence that malignant arrhythmia may occur before structural changes in inherited cardiomyopathy, so-called "concealed cardiomyopathy" (CCM).

Objectives: The authors sought to identify the spectrum of genes implicated in autopsy-inconclusive SCD and describe the impact of identifying CCM on the ongoing care of SCD families.

Methods: Using a standardized framework for adjudication, autopsy-inconclusive SCD cases were identified as having a structurally normal heart or subdiagnostic findings of uncertain significance on autopsy. Genetic variants were classified for pathogenicity using the American College of Medical Genetics and Genomics guidelines. Family follow-up was performed where possible.

Results: Twenty disease-causing variants were identified among 91 autopsy-inconclusive SCD cases (mean age 25.4 ± 10.7 years) with a similar rate regardless of the presence or absence of subdiagnostic findings (25.5% vs 18.2%; P = 0.398). Cardiomyopathy-associated genes harbored 70% of clinically actionable variants and were overrepresented in cases with subdiagnostic structural changes at autopsy (79% vs 21%; P = 0.038). Six of the 20 disease-causing variants identified were in genes implicated in arrhythmogenic cardiomyopathy. Nearly two-thirds of genotype-positive relatives had an observable phenotype either at initial assessment or subsequent follow-up, and 27 genotype-negative first-degree relatives were released from ongoing screening.

Conclusions: Phenotype-directed genetic testing following SCD risks under recognition of CCM. Comprehensive evaluation of the decedent should include assessment of genes implicated in cardiomyopathy in addition to primary arrhythmias to improve diagnosis of CCM and optimize care for families.

Keywords: autopsy-inconclusive; concealed cardiomyopathy; findings of uncertain significance; genetic testing; sudden cardiac death.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Arrhythmias, Cardiac / complications
Arrhythmias, Cardiac / diagnosis
Arrhythmias, Cardiac / genetics
Autopsy
Cardiomyopathies* / complications
Cardiomyopathies* / genetics
Death, Sudden, Cardiac* / epidemiology
Death, Sudden, Cardiac* / etiology
Death, Sudden, Cardiac* / pathology
Genetic Testing
Humans