Despite the difficulties of autopsy investigation and emerging evidence that malignant arrhythmia may begin before structural abnormalities in hereditary cardiomyopathy, or so-called “concealed cardiomyopathy,” (CCM) genetic testing after sudden cardiac death (SCD) is still governed by autopsy results. In addition to describing the effects of discovering CCM on the ongoing treatment of SCD families, researchers, for a study, attempted to determine the range of genes associated with autopsy-inconclusive SCD.

Autopsy-inconclusive SCD patients were recognized as having structurally normal heart or sub-diagnostic evidence of questionable significance on autopsy using a systematic methodology for adjudication. Using the criteria of the American College of Medical Genetics and Genomics, genetic variations were categorized for pathogenicity. Follow-up with the family was done when it was possible.

Regardless of the presence or absence of sub-diagnostic symptoms, twenty disease-causing variations were discovered among 91 autopsy-inconclusive SCD patients (mean age 25.4±10.7 years) at a comparable proportion (25.5% vs. 18.2%; P = 0.398). Genes linked to cardiomyopathy were overrepresented in patients with sub-diagnostic structural alterations at postmortem (79% versus 21%; P = 0.038), and they contained 70% of clinically actionable variations. Twenty disease-causing variations were found, and six were in genes linked to arrhythmogenic cardiomyopathy. Around 27 genotype-negative first-degree relatives were exempted from further screening because they had a visible phenotype in almost two-thirds of genotype-positive relatives at either the first assessment or a subsequent follow-up.

Genetic testing focused on phenotypes in the wake of SCD hazards under CCM. To improve the diagnosis of CCM and improve care for families, a thorough evaluation of the decedent should consider primary arrhythmias in addition to testing for genes linked to cardiomyopathy.

Reference: jacc.org/doi/10.1016/j.jacc.2022.09.029