Rare genetic mutations implicated in >13% of unexplained cardiac deaths. Makes one wonder how much of the long tail of deaths are due to rare variants, and how much of a benefit there would be to erasing the ~80k mutations everyone carries... (Population genetics rule: rare variants are more harmful than common variants; and 1 harmful mutation, 1 reproductive death to purge it from the population.) Very cool application of genetics.
"A Prospective Study of Sudden Cardiac Death among Children and Young Adults", Bagnall et al 2016:
"BACKGROUND: Sudden cardiac death among children and young adults is a devastating event. We performed a prospective, population-based, clinical and genetic study of sudden cardiac death among children and young adults.
METHODS: We prospectively collected clinical, demographic, and autopsy information on all cases of sudden cardiac death among children and young adults 1 to 35 years of age in Australia and New Zealand from 2010 through 2012. In cases that had no cause identified after a comprehensive autopsy that included toxicologic and histologic studies (unexplained sudden cardiac death), at least 59 cardiac genes were analyzed for a clinically relevant cardiac gene mutation.
RESULTS: A total of 490 cases of sudden cardiac death were identified. The annual incidence was 1.3 cases per 100,000 persons 1 to 35 years of age; 72% of the cases involved boys or young men. Persons 31 to 35 years of age had the highest incidence of sudden cardiac death (3.2 cases per 100,000 persons per year), and persons 16 to 20 years of age had the highest incidence of unexplained sudden cardiac death (0.8 cases per 100,000 persons per year). The most common explained causes of sudden cardiac death were coronary artery disease (24% of cases) and inherited cardiomyopathies (16% of cases). Unexplained sudden cardiac death (40% of cases) was the predominant finding among persons in all age groups, except for those 31 to 35 years of age, for whom coronary artery disease was the most common finding. Younger age and death at night were independently associated with unexplained sudden cardiac death as compared with explained sudden cardiac death. A clinically relevant cardiac gene mutation was identified in 31 of 113 cases (27%) of unexplained sudden cardiac death in which genetic testing was performed. During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 13% of the families in which an unexplained sudden cardiac death occurred.
CONCLUSIONS: The addition of genetic testing to autopsy investigation substantially increased the identification of a possible cause of sudden cardiac death among children and young adults.
Estimates in studies of the incidence of sudden cardiac death vary widely owing to differences in the age range of the various study populations; in addition, studies are often limited by small sample size and by retrospective and non–population-based study designs. A nationwide retrospective study of sudden cardiac death in an unselected population of persons 1 to 35 years of age in Denmark showed an incidence of 2.8 per 100,000 person-years, or 1.9 per 100,000 person-years when only autopsied cases were considered. 8 A similar incidence of 1.8 per 100,000 per year was found after a review of death certificates in England and Wales. 9 In up to one third of cases of sudden cardiac death among children and young adults, a cause of death is not found after a comprehensive autopsy examination that includes toxicologic and histologic studies; these deaths are termed un explained sudden cardiac deaths. 3,8,10-12 Unexplained sudden cardiac death is often attributed to cardiac arrhythmia caused by cardiac ionchannel dysfunction, which is undetectable in a conventional autopsy. Noncardiac conditions may also cause sudden death that is clinically indistinguishable from sudden cardiac death. For example, patients with epilepsy have a higher rate of sudden death than persons without epilepsy, and sudden unexpected death in epilepsy is the most common cause of death related to epilepsy. 13 Autopsy-based genetic studies of the major genes for the long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia (a four-gene “molecular autopsy” including the KCNQ1, KCNH2, SCN5A, and RYR2 genes) have identified a pathogenic mutation in up to one third of unexplained sudden cardiac deaths that were referred for postmortem genetic testing. 14,15 However, in population-based, nonreferred cases of unexplained sudden cardiac death, the prevalence of pathogenic mutations in the major genes for the long-QT syndrome is significantly lower. 16,17 Furthermore, population-based studies of human genetic variation have revealed an abundance of rare variants, which has led to increasingly stringent mutation classification criteria and a lower diagnostic yield of autopsy genetic testing for unexplained sudden cardiac death. 18,19 We performed a 3-year, prospective, population-based study of sudden cardiac death among persons 1 to 35 years of age in Australia and New Zealand and focused on determining the underlying cause of death after a comprehensive autopsy examination and genetic testing.
All major forensic pathology centers in Australia and New Zealand prospectively collected premorbid and autopsy investigation data on all cases of sudden cardiac death that occurred in persons 1 to 35 years of age from January 2010 through December 2012. Autopsy examinations were performed by the medical examiners at these centers according to the guidelines of the Royal College of Pathologists of Australasia. 20 In addition, case reports of deaths that had been investigated by a coroner were retrieved from the National Coronial Information System (for Australia) and the Case Management System (for New Zealand) and from the registries of births, deaths, and marriages in each Australian state and territory.
Coroners’ autopsy reports, which included toxicologic and histologic findings, and police reports of death were reviewed to identify cases of sudden cardiac death. Sudden cardiac death was defined as a sudden unexpected death in an otherwise healthy person within 1 hour after the onset of symptoms or, when unwitnessed, within 24 hours after the person was last seen in good health.
DNA was isolated from samples of whole blood obtained at autopsy, as described previously. 18 The genetic analysis of DNA in cases of unexplained sudden cardiac death is summarized in Figure 1. In 51 of the 113 cases of unexplained sudden cardiac death (45%), we performed clinical-grade sequencing (i.e., a next-generation sequencing test accredited through the National Association of Testing Authorities) of the coding exons of 69, 98, or 101 cardiac disease genes on the Illumina MiSeq platform (Victorian Clinical Genetic Services).
From 2010 through 2012, a total of 490 cases of sudden cardiac death were identified in persons 1 to 35 years of age; 360 (73%) were identified at 11 centers in Australia and 130 (27%) at 5 centers in New Zealand. Of the 490 cases of sudden cardiac death, 198 (40%) were unexplained. During the study period, the mean combined population of Australia and New Zealand was 26.74 million persons, of whom 12.59 million were 1 to 35 years of age. 23 On the basis of these figures, the annual incidence of sudden cardiac death in Australia and New Zealand was 1.3 cases per 100,000 persons (95% confidence interval, 1.2 to 1.4); men and boys had a higher incidence than did women and girls (1.8 vs. 0.7 cases per 100,000 persons, P<0.001). Persons 31 to 35 years of age had the highest incidence of sudden cardiac death (3.2 cases per 100,000 persons), and persons 16 to 20 years of age had the highest incidence of unexplained sudden cardiac death (0.8 cases per 100,000 persons) (Fig. 2A).
A definite clinical diagnosis was established in 12 of the 91 families (13%) that underwent follow-up clinical screening; inherited arrhythmogenic diseases were identified in 7 families (the long-QT syndrome in 4, catecholaminergic polymorphic ventricular tachycardia in 1, the short-QT syndrome in 1, and primary conduction disease in 1) and inherited cardiomyopathies were identified in 5 families (arrhythmogenic right ventricular cardiomyopathy in 2 and dilated cardiomyopathy, left ventricular noncompaction, or both in 3)."