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SIDS may result from inherited cardiac conditions such as the primary arrhythmia syndromes, a heterogeneous group of genetic cardiacion channelopathies that predispose to ventricular arrhythmia and sudden death in the setting of a structurally normal heart. This is very much in keeping with the normal autopsy findings expected in SIDS. The channelopathies are mainly inherited in an autosomal dominant manner and are often caused by mutations in genes encoding cardiac ion-channel subunits or channel-interacting proteins. They include long QT syndrome (LQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). The relationship between cardiac channelopathies and SIDS has largely relied on post-mortem genetic studies, the ‘molecular autopsy’. Causation has been proposed by the discovery of putative ‘pathogenic’rare variants in candidate cardiac genes (see Figure 29.1 and Table 2.9). These variants either have established disease association or, more commonly, a presumed effect on disease expression backed up by in vitro experimental data and/or in silico tools for assessing pathogenicity. The accuracy of these methods is however variable.[1]

It is increasingly recognised that mutations in SIDS may arise de novo and are associated with a more malignant clinical phenotype, manifesting in early-onset disease in keeping with a number of severe paediatric neurodevelopment disorders.[2] While our understanding of the complexity of cardiac genetic susceptibility in SIDS continues to evolve, recent guidelines include post-mortem genetic testing alongside familial evaluation in cases …