Genetic Analysis of Sudden Death Victims and Their Relatives
Abstract & Commentary
By John P. DiMarco, MD, PhD
Source: van der Werf C, et al. Diagnostic yield in sudden unexplained death and aborted cardiac arrest in the young: The experience of a tertiary referral center in The Netherlands. Heart Rhythm. 2010;7:1383-1389.
In this paper, Van der Werf and colleagues from the University of Groningen report the diagnostic yield of comprehensive cardiologic and genetic examinations in surviving relatives of sudden, unexplained death victims and in victims of cardiac arrest where the event occurred between the age of 1 and 50 years. This was a single-center study from a tertiary referral hospital that included either patients referred to the institution or with genetic analysis after unexplained sudden death of a first- or second-degree relative or patients with aborted cardiac arrest at the author's institution or within their catchment area. Standard criteria for unexplained cardiac death and cardiac arrest were used and a diagnosis of the cause of death could be made at autopsy. Subjects with identifiable noncardiac etiologies of aborted cardiac arrest were not included. Data concerning the cardiac arrest were obtained for all sudden-death index cases. For every sudden-death victim's relative, a 12-lead ECG was recorded at their first visit. If an autopsy had been performed at another center, tissue samples were reviewed by a specialized cardiovascular pathologist. Frozen tissue, if available, was collected for DNA isolation from the victim. Testing in relatives was selective based on the victim's clinical information and the resting ECG data.
All aborted cardiac-arrest victims received a very detailed evaluation including resting ECG, continuous heart rhythm monitoring, and echocardiography. Pharmacologic challenge with ajmaline and or flecainide was performed when the Brugada syndrome was suspected. Coronary angiography was performed when indicated. Exercise testing was performed if a long QT syndrome or catecholaminergic polymorphic ventricular tachycardia was suspected and/or the event occurred during exercise. When arrhythmogenic right ventricular cardiomyopathy was suspected, cardiac magnetic resonance imaging was performed. Genetic assessment was performed in a targeted manner after review of the clinical data. The genes for known ion channelopathies or Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, and hypertrophic cardiomyopathy were scanned for associated mutations.
The study eventually included the surviving relatives of 140 sudden, unexpected death victims and 59 aborted cardiac-arrest victims. A total of 650 living first- and second-degree relatives of the sudden, unexplained death victims were examined. In 47 of 140 families, a probable diagnosis was made. When examined by the age of the sudden, unexplained death victim, the diagnostic yield was 71% when the event occurred between 0 and 10 years, 38% in the age group 11 to 20 years, 39% in the age group 21 to 30 years, 29% in the age group of 31 to 40 years, and 21% in the age of 41 to 49 years. In 45 of 47 families, the diagnosis was an inherited cardiac disease. Long QT syndrome (n = 10) [21%] was the most frequent diagnosis, followed by catecholaminergic polymorphic ventricular tachycardia (n = 8, [17%]), Brugada syndrome (n = 7, [15%]), and arrhythmogenic right ventricular cardiomyopathy, (n = 6, [13%]). There also were two cases of myocarditis. In addition, an abnormality on chromosome 7q36 at the locus, which has been associated with familial idiopathic ventricular fibrillation, was identified in four patients. Diagnosis was age-dependent. A primary arrhythmia syndrome was the most common diagnosis when the victim was under age 14. Cardiomyopathies became more common between age 14 and 30. Premature coronary disease was more common in the age group of 30 to 49 years. In the remaining 94 families, sudden death remained unexplained. Among the aborted cardiac-arrest victims, certain or probable diagnosis was made in 42 (61%). In this group, the most frequent cause of aborted cardiac arrest was hypertrophic cardiomyopathy (n = 7, [70%]), followed by myocardial infarction, (n = 6, [14%]), long QT syndrome (n=5, [12%]), Brugada syndrome (n = 5, [12%]), and arrhythmogenic right ventricular dysplasia (n = 5, [12%]). Two patients with aborted cardiac arrest due to myocardial infarction had an inherited familial hypercholesterolemia. The idiopathic ventricular fibrillation risk locus on chromosome 7q36 was identified in four patients. Among the sudden, unexplained death victims, the presence of a previous early cardiac arrest in another first-degree relative was a predictor of positive findings. In the aborted cardiac-arrest victims, clinical factors identified those in whom a positive finding was likely to be made.
The authors conclude that thorough cardiologic and genetic evaluation of relatives of sudden, unexplained death victims will yield positive findings in one-third of the cases. A similar protocol will give a 60% positive yield in survivors of cardiac arrest. Inherited cardiac diagnoses associated with sudden death are the most common positive findings.
Commentary
Unexpected sudden death among the young has long both fascinated and terrified cardiologists. Over the last several years, tremendous progress has been made in elucidating the various syndromes that are associated with this phenomenon.
Management of family members of young sudden-death victims has often been difficult. In this paper, the authors show that a systematic genetic and cardiac evaluation can yield a positive diagnosis in many cases. Once the etiology for sudden death in the index case is known, family members can be tested. For those identified to share the condition, appropriate genetic counseling and therapy can be prescribed.
In this paper, Van der Werf and colleagues from the University of Groningen report the diagnostic yield of comprehensive cardiologic and genetic examinations in surviving relatives of sudden, unexplained death victims and in victims of cardiac arrest where the event occurred between the age of 1 and 50 years.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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