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June 27, 2026Journal of the American College of Cardiology

Genetic testing in autopsy-inconclusive sudden cardiac death identified disease-causing variants in 22% of cases, with similar rates in those with and without subdiagnostic findings (25.5% vs 18.2%).

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Why the study?

Does comprehensive genetic testing including cardiomyopathy genes improve the diagnosis of concealed cardiomyopathy in autopsy-inconclusive sudden cardiac death cases?

Population

91 autopsy-inconclusive sudden cardiac death cases with a structurally normal heart or subdiagnostic…

Design

Cohort

Key result

Genetic testing in autopsy-inconclusive sudden cardiac death identified disease-causing variants in 22% of cases, with similar rates in those with and without subdiagnostic findings (25.5% vs 18.2%).

Authors

JIJulia C. IsbisterNNNatalie NowakLYLaura Yeates

Discussion

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Key expert perspectives

Captured external expert commentary on this paper, strongest first. Original sources are linked where available.

JIJulia IsbisterResearcher, Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

“We believe that the genetic testing of sudden cardiac death cases which are unexplained after autopsy should be broader so that we can identify concealed cardiomyopathy. Identifying the cause of death also helps us provide optimal care for surviving relatives.”

Centenary InstituteNews Coverage
CSChristopher SemsarianCardiologist, Royal Prince Alfred Hospital and University of Sydney

“Our research highlights the wide spectrum of genes implicated in autopsy-inconclusive sudden cardiac death and the importance of identifying concealed cardiomyopathy for the ongoing care of sudden cardiac death families.”

Centenary Institute / University of SydneyNews Coverage
JIJulia IsbisterResearcher, Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

“Identifying concealed cardiomyopathy meant that we found the cause of the young person's death in 14 more families than we would have in this cohort if we hadn't looked at cardiomyopathy genes.”

Centenary InstituteNews Coverage

Overview

May support genetic testing after inconclusive SCD autopsy; leaves open prospective validation of family screening protocols.

Key Points

  • This research aims to explore genetic factors in sudden cardiac death cases with inconclusive autopsy findings and the consequences for family care.
  • Standardized framework used to identify autopsy-inconclusive sudden cardiac death cases.
  • Genetic variants classified following American College of Medical Genetics and Genomics guidelines.
  • Follow-up conducted with families where applicable.
  • Twenty disease-causing variants identified in 91 inconclusive SCD cases (mean age 25.4 years).
  • Seventy percent of clinically actionable variants were in cardiomyopathy-associated genes, especially in those with subdiagnostic findings (79% vs 21%, P = 0.038).
  • Approximately two-thirds of genotype-positive relatives exhibited observable phenotypes, while 27 genotype-negative relatives discontinued screening.

Study Design

Type

Observational (n=91)

Structured PICO

Does comprehensive genetic testing including cardiomyopathy genes improve the diagnosis of concealed cardiomyopathy in autopsy-inconclusive sudden cardiac death cases?

P
Population
91 autopsy-inconclusive sudden cardiac death cases (mean age 25.4 years) with structurally normal hearts or subdiagnostic findings evaluated with genetic testing.
E
Exposure
Comprehensive genetic testing including assessment of genes implicated in cardiomyopathy and primary arrhythmias.
O
Outcome
Identification of disease-causing genetic variants and the impact of identifying concealed cardiomyopathy on the ongoing care of SCD families.

Main Result

Absolute Event Rate: 25.5% vs 18.2%

p-value: p=0.398

Comprehensive genetic testing including cardiomyopathy genes in autopsy-inconclusive sudden cardiac death cases identifies a significant proportion of concealed cardiomyopathies, aiding in the diagnosis and management of surviving relatives.

Cite This Study

Isbister et al. (2022) conducted an observational in Autopsy-inconclusive sudden cardiac death (n=91). Presence of subdiagnostic findings at autopsy vs. Absence of subdiagnostic findings was evaluated on Identification of disease-causing variants (p=0.398). Genetic testing in autopsy-inconclusive sudden cardiac death identified disease-causing variants in 22% of cases, with similar rates in those with and without subdiagnostic findings (25.5% vs 18.2%).

synapsesocial.com/papers/6a403e4be87d0bf28331a0c2https://doi.org/10.1016/j.jacc.2022.09.029
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