Abstract
Sudden cardiac death (SCD) in people before the age of 35 years is a devastating event for any family. The causes of SCD in the young can be broadly divided into two groups: heritable cardiac disorders that affect the heart structure (cardiomyopathies) and primary electrical disorders (cardiac ion channelopathies). Genetic testing is vital as those suffering from cardiac ion channelopathies have structurally normal hearts, and those with cardiomyopathies may only show subtle abnormalities in the heart and these signs may not be detected during an autopsy. Post-mortem genetic testing of SCD victims is important to identify the underlying genetic cause. This is important as family cascade screening may be undertaken to identify those who may be at risk and provide vital information about risk stratification and clinical management. The development of massively parallel sequencing (MPS) has made it possible for the simultaneous screening of multiple patients for hundreds of genes. In light of this, we opted to develop an MPS approach for SCD analysis that would allow us to screen for mutations in genes implicated in cardiomyopathies and cardiac ion channelopathies. The rationale behind this panel was to limit it to genes carrying the greatest mutation load. If no likely pathogenic gene variant were found then testing could cascade to whole exome/genome sequencing as a gene-discovery exercise. The overarching aim was to design and validate a custom-cardiac panel that satisfies the diagnostic requirements of LabPLUS (Auckland City Hospital, Auckland, NZ) and the guidelines provided by the Royal College of Pathologists of Australasia and the Association for Clinical Genetic Science.
Highlights
Sudden cardiac death (SCD) in people before the age of 35 years is a devastating event for any family, and it has a yearly incidence of 0.005–0.2 per 1000 [1,2]
The heritable causes of SCD in the young can be broadly divided into two groups: cardiac disorders that affect the heart structure, and primary electrical disorders
The testing at LabPLUS involved Sanger-based sequencing of the coding regions of genes implicated in LongQT syndrome (LQTS) 1, 2, 3, 5, 6 and 7, and the testing at The Churchill Hospital involved an massively parallel sequencing (MPS) approach that comprised hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) panels
Summary
Sudden cardiac death (SCD) in people before the age of 35 years is a devastating event for any family, and it has a yearly incidence of 0.005–0.2 per 1000 [1,2]. Genetic testing, combined with cardiac screening of relatives [6,7], are vital for these disorders as the heart is structurally normal and would not be diagnosed at autopsy [8,9] Cardiomyopathies, such as hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM), become more common as a cause of death from teenage years onwards [3]. Post-mortem genetic testing (molecular autopsy) uses DNA extracted from blood/tissue of SCD victims to identify the underlying genetic cause of death in SCD cases This is important as family cascade screening may be undertaken to identify those who may be at risk and provide vital information about risk stratification and clinical management [10]
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