Key result
Molecular autopsy identifies deleterious cardiomyopathy variants in ~10% of autopsy-inconclusive childhood sudden death cases.
Why the study?
Unexplained sudden death remains a challenge in childhood, with some autopsies revealing rare cardiomyopathy-associated gene variants in structurally normal hearts, suggesting concealed cardiomyopathy.
Observational (n=68)
May support molecular autopsy in unexplained childhood sudden deaths; leaves open routine adoption pending validation studies.
One of the ongoing challenges in childhood remains the unexplained sudden death. Autopsies identify a subset of cases that harbor rare variants in genes associated with cardiomyopathy in structurally normal hearts, suggesting a concealed cardiomyopathy. Our goal is to interpret all available data in each case to provide answers to unexplained deaths, while also implementing preventative measures for at-risk family members. Our retrospective study included 68 childhood cases of sudden death, classified as inconclusive at autopsy. Molecular autopsy analyzed all genes currently associated with inherited arrhythmogenic syndromes. Variants were reinterpreted according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Seventeen autopsy-inconclusive childhood cases (70.59% males) carried at least one rare variant in any of the cardiomyopathy-susceptibility genes. A definite deleterious variant was identified in seven cases (10.3%), whereas ten (14.7%) carried only variants of uncertain significance. Slight non-diagnostic myocardial alterations were identified in five cases (7.35%), and three of them carried a deleterious variant. Clinical and genetic analyses of all families identified a carrier of deleterious variants with a diagnosis of cardiomyopathy in six of them (8.82%). Our data support the inclusion of a comprehensive analysis of all genes associated with inherited cardiomyopathies in childhood cases of unexpected death. A personalized multidisciplinary interpretation of post-mortem and genetic data, including family assessment, helps to clarify the role of rare variants and determine the most plausible cause of the unexpected death in one-tenth of the childhood individuals.
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Greco et al. (2026) conducted an observational in unexplained sudden childhood death (n=68). Molecular autopsy analyzing genes associated with inherited arrhythmogenic syndromes was evaluated on Identification of a definite deleterious variant in cardiomyopathy-susceptibility genes. Molecular autopsy identified a definite deleterious variant in cardiomyopathy-susceptibility genes in 10.3% of autopsy-inconclusive childhood sudden death cases.