Molecular autopsy in victims of inherited arrhythmias

Abstract

Sudden cardiac death (SCD) is a rare but devastating complication of a number of underlying cardiovascular diseases. While coronary artery disease and acute myocardial infarction are the most common causes of SCD in older populations, inherited cardiac disorders comprise a substantial proportion of SCD cases aged less than 40 years. Inherited cardiac disorders include primary inherited arrhythmogenic disorders such as familial long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and inherited cardiomyopathies, most commonly hypertrophic cardiomyopathy (HCM). In up to 40% of young SCD victims (defined as 1-40 years old, excluding sudden unexplained death in infancy from 0 to 1 years, referred to as SIDS), no cause of death is identified at postmortem [so-called "autopsy negative" or "sudden arrhythmic death syndrome" (SADS)]. Management of families following a SCD includes the identification of the cause of death, based either on premorbid clinical details or the pathological findings at the postmortem. When no cause of death is identified, genetic testing of DNA extracted from postmortem tissue (the molecular autopsy) may identify a cause of death in up to 30% of SADS cases. Targeted clinical testing in a specialized multidisciplinary clinic in surviving family members combined with the results from genetic testing, provide the optimal setting for the identification of relatives who may be at risk of having the same inherited heart disease and are therefore also predisposed to an increased risk of SCD.

Keywords: Genetics; Molecular autopsy; Postmortem; Specialized multidisciplinary clinic; Sudden cardiac death.

Fig. 1

Causes of sudden cardiac death in the young (0–40 years) based on postmortem findings. SADS=sudden arrhythmic death syndrome, LQTS=long QT syndrome, CPVT1=catecholaminergic polymorphic ventricular tachycardia type 1, HCM=hypertrophic cardiomyopathy, ARVC=arrhythmogenic right ventricular cardiomyopathy.

Fig. 2

Evaluation of families in the setting of a sudden cardiac death in a young family member. Genetic testing is often performed concurrently with clinical evaluation of family members. This figure is modified from Semsarian et al. .

Fig. 3

Role of CT scanning and cardiac magnetic resonance imaging postmortem. Diagnosis of arrhythmogenic right ventricular cardiomyopathy (A, B), hypertrophic cardiomyopathy (C, D), acute coronary occlusion, and myocardial infarction (E, F) based on histological and imaging analyses. This figure was modified from Puranik et al. .

Fig. 4

Steps in the molecular autopsy process. DNA is extracted from blood collected at postmortem. Subsequent DNA analysis of selected genes is done by Sanger sequencing or newer parallel next generation sequencing platforms. This figure was modified from Semsarian et al. .

Fig. 5

Clinical investigation pathway of surviving family members when no cause of death is identified. CMR=cardiac magnetic resonance, ECG=electrocardiogram, SAECG=signal averaged ECG. This figure was modified from Priori et al. .

Fig. 6

Specialized multidisciplinary approach to caring for families with a sudden cardiac death in a young family member. PCP=primary care physician. This figure was modified from Ingles et al. .