Whole-Exome Molecular Autopsy After Exertional Sudden Cardiac Death
Not a Panacea but a Step in the Right Direction
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The sudden death of a seemingly healthy child is a loss from which many families never recover. Despite a Medical Examiner’s autopsy, a significant proportion of such deaths remain unexplained or ascribed to natural causes, a conclusion that only exacerbates the deep sense of confusion, disbelief, and continued distress faced by the family.1 Identification of the underlying cause behind sudden cardiac death in the young not only provides an explanation for the family, but given the high likelihood of a genetic cause facilitates testing in first-degree family members and the implementation of protective measures in those considered at risk.
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When faced with a negative conventional autopsy, a molecular autopsy therefore provides a welcome second line of investigation, a strategy deemed worthy of consideration in the 2011 joint expert consensus statement by the Heart Rhythm Society and European Heart Rhythm Association.2 A comprehensive molecular analysis on exertional sudden death cases, as performed by Anderson et al3 from the Mayo Clinic and reported in this edition of Circulation Cardiovascular Genetics, adds further understanding to potential causal mechanisms that underlie sudden death in children. The association between cardiac arrhythmia and exercise is firmly established for both long-QT syndrome type 1 (LQTS1) and catecholaminergic polymorphic ventricular tachycardia (CPVT), typically leading to exertional syncope or seizures,4,5 although sudden death as the sentinel event is well recognized. The clinical diagnosis is made electrocardiographically in both LQTS1 and CPVT, and cardiac pathological and histological examination will by definition be normal, making these attractive cases for molecular autopsy. Given that the molecular architecture for LQTS1 and CPVT is better understood than for many other cardiovascular genetic disorders and the phenotype can be elicited in surviving relatives, identified variants in 2 major disease-associated genes, KCNQ1 or RyR2, …