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

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

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Item Type: Article
Status: Published
Official URL:
Journal or Publication Title: Journal of the American College of Cardiology
Volume: 80
Number: 22
Page Range: pp. 2057-2068
Date: 29 November 2022
Divisions: Molecular Cardiology
Depositing User: General Admin
Identification Number: 10.1016/j.jacc.2022.09.029
ISSN: 07351097
Date Deposited: 15 Mar 2023 23:41

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.

Isbister, Julia C.
Nowak, Natalie
Yeates, Laura
Singer, Emma S.
Sy, Raymond W.
Ingles, Jodie
Raju, Hariharan
Bagnall, Richard D.
Semsarian, Christopher
Last Modified: 15 Mar 2023 23:41

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