The Molecular Autopsy: Should the Evaluation Continue After the Funeral?

Division of Cardiovascular Diseases, Department of Medicine, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, Rochester, MN, USA.
Pediatric Cardiology (Impact Factor: 1.31). 03/2012; 33(3):461-70. DOI: 10.1007/s00246-012-0160-8
Source: PubMed


Sudden cardiac death (SCD) is one of the most common causes of death in developed countries, with most SCDs involving the elderly, and structural heart disease evident at autopsy. Each year, however, thousands of sudden deaths involving individuals younger than 35 years of age remain unexplained after a comprehensive medicolegal investigation that includes an autopsy. In fact, several epidemiologic studies have estimated that at least 3% and up to 53% of sudden deaths involving previously healthy children, adolescents, and young adults show no morphologic abnormalities identifiable at autopsy. Cardiac channelopathies associated with structurally normal hearts such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) yield no evidence to be found at autopsy, leaving coroners, medical examiners, and forensic pathologists only to speculate that a lethal arrhythmia might lie at the heart of a sudden unexplained death (SUD). In cases of autopsy-negative SUD, continued investigation through either a cardiologic and genetic evaluation of first- or second-degree relatives or a molecular autopsy may elucidate the underlying mechanism contributing to the sudden death and allow for identification of living family members with the pathogenic substrate that renders them vulnerable, with an increased risk for cardiac events including syncope, cardiac arrest, and sudden death.

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Available from: Michael John Ackerman, Feb 14, 2014
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    • "The most challenging type of SCD occurs when it cannot be traced to any evident cause other than a lethal arrhythmia, which may represent the sole sentinel event of an otherwise silent disease [1,2]. Congenital cardiac channelopathies and cardiomyopathies are known to play significant roles in SCD [2-4]. "
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    ABSTRACT: Background Sudden cardiac death (SCD) is the clinical outcome of a lethal arrhythmia that can develop on the background of unrecognized channelopathies or cardiomyopathies. Several susceptibility genes have been identified for the congenital forms of these cardiac diseases, including caveolin-3 (Cav-3) gene. In the heart Cav-3 is the main component of caveolae, plasma membrane domains that regulate multiple cellular processes highly relevant for cardiac excitability, such as trafficking, calcium homeostasis, signal transduction and cellular response to injury. Here we characterized a new putative Cav-3 variant, Cav-3 V82I, found in a patient with SCD. Results In heterologous systems Cav-3 V82I was expressed at significantly higher level than Cav-3 WT and accumulated within the cells. Cells expressing Cav-3 V82I exhibited a decreased activation of extracellular-signal-regulated kinases (ERKs) and were more vulnerable to sub-lethal osmotic stress. Conclusion Considering that abnormal loss of myocytes can play a mechanistic role in lethal cardiac diseases, we suggest that the detrimental effect of Cav-3 V82I variant on cell viability may participate in determining the susceptibility to cardiac death.
    Full-text · Article · Jun 2014 · Journal of Biomedical Science
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    • "A report in 2009 found that sudden cardiac death was responsible for ~60,000 deaths, with ischemic heart disease the major cause (Papadakis et al., 2009). In the younger population (1–35 years of age), sudden cardiac death is the most common cause of premature death (Tester and Ackerman, 2012). Here, a thorough investigation including autopsy is critical in identifying a cause—for instance, structural abnormalities such as cardiomyopathies [e.g., hypertrophic cardiomyopathy (HCM)] may be identified at the point of autopsy. "
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    ABSTRACT: SADS is defined as sudden death under the age of 40 years old in the absence of structural heart disease. Family screening studies are able to identify a cause in up to 50% of cases-most commonly long QT syndrome (LQTS), Brugada and early repolarization syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT) using standard clinical screening investigations including pharmacological challenge testing. These diagnoses may be supported by genetic testing which can aid cascade screening and may help guide management. In the current era it is possible to undertake molecular autopsy provided suitable samples of DNA can be obtained from the proband. With the evolution of rapid sequencing techniques it is possible to sequence the whole exome for candidate genes. This major advance offers the opportunity to identify novel causes of lethal arrhythmia but also poses the challenge of managing the volume of data generated and evaluating variants of unknown significance (VUS). The emergence of induced pluripotent stem cell technology could enable evaluation of the electrophysiological relevance of specific ion channel mutations in the proband or their relatives and will potentially enable screening of idiopathic ventricular fibrillation survivors combining genetic and electrophysiological studies in derived myocytes. This also could facilitate the assessment of personalized preventative pharmacological therapies. This review will evaluate the current screening strategies in SADS families, the role of molecular autopsy and genetic testing and the potential applications of molecular and cellular diagnostic strategies on the horizon.
    Full-text · Article · Sep 2013 · Frontiers in Physiology
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    Full-text · Article · Aug 2012 · Pediatric Cardiology
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