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

https://doi.org/10.1016/j.jacc.2022.09.029Get rights and content
Under an Elsevier user license
open archive

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). Nine 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.

Key Words

autopsy-inconclusive
concealed cardiomyopathy
findings of uncertain significance
genetic testing
sudden cardiac death

Abbreviations and Acronyms

ACM
arrhythmogenic cardiomyopathy
BrS
Brugada syndrome
CCM
concealed cardiomyopathy
CM
cardiomyopathy
HCM
hypertrophic cardiomyopathy
IAS
inherited arrhythmia syndrome
SCD
sudden cardiac death
VUS
variant of uncertain significance

Cited by (0)

Listen to this manuscript's audio summary by Editor-in-Chief Dr Valentin Fuster on www.jacc.org/journal/jacc.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.