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%).
Observational (n=91)
Does comprehensive genetic testing including cardiomyopathy genes improve the diagnosis of concealed cardiomyopathy in autopsy-inconclusive sudden cardiac death cases?
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.
Absolute Event Rate: 25.5% vs 18.2%
p-value: p=0.398
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.
“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.”
Isbister et al. (Tue,) conducted a 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%).