Concealed cardiomyopathy in sudden childhood death: translation from molecular autopsy to family assessment.

Rare variants in cardiomyopathy genes in structurally normal hearts — molecular autopsy and ACMG/AMP reinterpretation completed by family assessment

Sixty-eight childhood sudden death cases classified as inconclusive at autopsy underwent molecular autopsy covering all genes associated with inherited arrhythmogenic syndromes, with variant reinterpretation according to ACMG/AMP guidelines. Seventeen cases (70.59% male) carried at least one rare variant in a cardiomyopathy-susceptibility gene: seven (10.3%) a definite deleterious variant, ten (14.7%) only variants of uncertain significance. Slight non-diagnostic myocardial alterations were present in five cases (7.35%), three of which carried a deleterious variant. Clinical and genetic assessment of all families identified, in six of them (8.82%), a relative carrying a deleterious variant with a diagnosis of cardiomyopathy.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The contribution is the method rather than the yield: it is the combination of histology, variant data and relative assessment that turns a rare variant into a plausible explanation — six families here had a living carrier diagnosed. The corollary is the rate of variants of uncertain significance, higher than that of conclusive variants, which leaves bereaved families with a heavy uncertainty. A retrospective single-centre series of 68 cases: these proportions do not extrapolate.

Analysis by Dr Thibaut Benquey