This 3-year prospective, population-based study of sudden cardiac death among persons 1 to 35 years of age in Australia and New Zealand identified 490 cases of sudden cardiac death, representing an incidence rate of 1.3 cases per 100,000 persons per year. The most common finding after autopsy was unexplained sudden cardiac death, which accounted for a larger proportion of cases of sudden cardiac death than did explained sudden cardiac death in younger age groups and among persons who died during nighttime hours (6 p.m. to 6 a.m.). Genetic analysis of 4 molecular autopsy genes revealed pathogenic and probably pathogenic variants in 9% of the cases of unexplained sudden cardiac death. Genetic analysis of an additional 55 cardiac genes in the cases of unexplained sudden cardiac death resulted in an overall diagnostic yield of 27%. Therefore, autopsy investigation combined with genetic testing and family screening was associated with a substantially higher likelihood of identifying a possible cause of sudden cardiac death among children and young adults than did autopsy investigation alone.

The incidence and underlying causes of death in our study varied according to age group. A total of 10% of all the cases of sudden cardiac death in our study occurred among children 1 to 5 years of age; most of these deaths occurred among infants and young children 1 to 2 years of age. Sudden cardiac death among infants and young children 1 to 2 years of age probably has shared causes with the sudden infant death syndrome, which is classified as the unexplained death of an infant younger than 1 year of age.24-27 Children 6 to 10 years of age had the lowest rate of sudden cardiac death (0.8%), after which the risk increased, as reported previously.28,29 The incidence of cardiomyopathy (hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy) as a cause of sudden cardiac death among children and young adults in our study was lower than that observed in previous studies30; this finding may reflect improved diagnosis and management in recent years, including the appropriate use of implantable cardioverter–defibrillator therapy.31-33 Coronary artery disease was the most common finding among persons 31 to 35 years of age.

A clinically important finding was that the majority of sudden cardiac deaths occurred either while the person was sleeping or at rest. This observation raises questions about the efficacy of limiting physical activity as a means of reducing the risk of sudden death among children and young adults, as is sometimes recommended for competitive athletes. Death during sleep may be caused by bursts of vagal and sympathetic activity during rapid-eye-movement sleep that lead to adrenergically triggered arrhythmias, although nonadrenergic mechanisms may also be involved. Therefore, strategies to prevent sudden cardiac death among children and young adults should also focus on gaining a better understanding of the mechanisms associated with death that occurs while a person is sleeping or at rest.

The likelihood that a case of unexplained sudden cardiac death was caused by an underlying inherited disorder has led to the emerging role of genetic testing of DNA obtained at autopsy (i.e., molecular autopsy).5,34 Establishing a clear genetic diagnosis in cases of unexplained sudden cardiac death has major implications for the identification of at-risk relatives, the initiation of strategies to prevent sudden death, and guidance with respect to reproductive options. In the current study, the diagnostic yield of 9% that was found for the four molecular autopsy genes is consistent with that found in unselected cohorts in previous studies (9 to 11%).16,17 In retrospective studies of unexplained sudden cardiac death in selected populations, there was a higher diagnostic yield (>20%), which may represent ascertainment and referral bias.14,15 We recently reported the genetic findings in 61 cases of sudden unexplained death in epilepsy; we found pathogenic or probably pathogenic variants in the three common genes for the long-QT syndrome in 7% of the cases and in epilepsy genes in 25% of the cases.35 In contrast, in the current study involving persons who had no history of epilepsy, we found only 4 cases of unexplained sudden cardiac death (6%) in which the person had probable pathogenic variants in epilepsy genes, which suggests that undiagnosed genetic epilepsy is uncommon in cases of unexplained sudden cardiac death.

In the current study, in the clinical follow-up of families in which an unexplained sudden cardiac death occurred, 12 of the families (13%) had a definite clinical diagnosis established in a first-degree relative; inherited cardiomyopathies were identified in five of these families. This diagnostic yield from clinical follow-up was less than what had been reported previously7,36 and probably reflects the population-based nature of our study, as compared with retrospective, tertiary center–based studies. A thorough clinical evaluation of surviving at-risk family members is nonetheless strongly recommended and may be supplemented by a molecular autopsy.4,6,37,38

Our study has several limitations. First, although every available national resource was used to identify cases of sudden cardiac death over the 3-year study period, some cases were not considered because our study did not include cases that had insufficient details to determine with certainty whether the death was sudden, and cases in which the body was found more than 24 hours after the person was last seen alive were not included. Second, various methodologic approaches to genetic analysis were used during the study, which reflects the rapid escalation in genetic technologies over the course of the study. Finally, the scope of the current study did not include cases of successfully resuscitated out-of-hospital cardiac arrest.

In conclusion, in this prospective, population-based, binational study, we found an annual incidence of sudden cardiac death of 1.3 cases per 100,000 persons 1 to 35 years of age. Unexplained sudden cardiac death accounted for 40% of the cases. Among the cases of unexplained sudden cardiac death in which genetic testing was performed, a likely cause of death was identified in 27%. Autopsy investigation combined with genetic testing and family screening was associated with a substantially higher likelihood of identifying a possible cause of death among children and young adults who had a sudden cardiac death than was autopsy investigation alone.