The molecular autopsy: an indispensable step following sudden cardiac death in the young?

Boczek, Nicole J.; Tester, David J.; Ackerman, Michael J.

doi:10.1007/s00399-012-0222-x

Cited by 31 publications

(28 citation statements)

References 40 publications

(64 reference statements)

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“…In contrast, SCD in the young-adult population (<35 years old) is often caused by arrhythmic syndromes with or without structural heart alterations. These diseases result from genetic alternations, which can be inherited [15]. Cardiomyopathies, such as hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic cardiomyopathy (AC) are characterized by the presence of structural heart alterations that lead to SCD-related arrhythmias.…”

Section: Introductionmentioning

confidence: 99%

Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances

Fernández-Falgueras

Sarquella-Brugada

Brugada

et al. 2017

Biology

109

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Sudden cardiac death poses a unique challenge to clinicians because it may be the only symptom of an inherited heart condition. Indeed, inherited heart diseases can cause sudden cardiac death in older and younger individuals. Two groups of familial diseases are responsible for sudden cardiac death: cardiomyopathies (mainly hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) and channelopathies (mainly long QT syndrome, Brugada syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia). This review focuses on cardiac channelopathies, which are characterized by lethal arrhythmias in the structurally normal heart, incomplete penetrance, and variable expressivity. Arrhythmias in these diseases result from pathogenic variants in genes encoding cardiac ion channels or associated proteins. Due to a lack of gross structural changes in the heart, channelopathies are often considered as potential causes of death in otherwise unexplained forensic autopsies. The asymptomatic nature of channelopathies is cause for concern in family members who may be carrying genetic risk factors, making the identification of these genetic factors of significant clinical importance.

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Section: Introductionmentioning

confidence: 99%

Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances

Fernández-Falgueras

Sarquella-Brugada

Brugada

et al. 2017

Biology

109

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“…1 Many of these deaths can be attributed to coronary artery disease; however, a small portion are caused by inherited structural heart diseases, such as hypertrophic cardiomyopathy (HCM) or structurally normal heart inherited arrhythmia syndromes, such as long QT syndrome (LQTS). 2, 3 Although both HCM and LQTS can cause sudden death due to cardiac arrhythmias, the pathophysiology, disease progression, and underlying molecular/genetic substrates are thought to be distinct.…”

Section: Introductionmentioning

confidence: 99%

Identification and Functional Characterization of a Novel CACNA1C -Mediated Cardiac Disorder Characterized by Prolonged QT Intervals With Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death

Boczek

Jin

et al. 2015

Circ: Arrhythmia and Electrophysiology

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Background A portion of sudden cardiac deaths (SCD) can be attributed to structural heart diseases such as hypertrophic cardiomyopathy (HCM) or cardiac channelopathies such as long QT syndrome (LQTS); however, the underlying molecular mechanisms are quite distinct. Here, we identify a novel CACNA1C missense mutation with mixed loss-of-function/gain-of-function responsible for a complex phenotype of LQTS, HCM, SCD, and congenital heart defects (CHDs). Methods and Results Whole exome sequencing (WES) in combination with Ingenuity Variant Analysis was completed on three affected individuals and one unaffected individual from a large pedigree with concomitant LQTS, HCM, and CHDs and identified a novel CACNA1C mutation, p.Arg518Cys, as the most likely candidate mutation. Mutational analysis of exon 12 of CACNA1C was completed on 5 additional patients with a similar phenotype of LQTS plus a personal or family history of HCM-like phenotypes, and identified two additional pedigrees with mutations at the same position, p.Arg518Cys/His. Whole cell patch clamp technique was used to assess the electrophysiological effects of the identified mutations in CaV1.2, and revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current. Conclusions Through WES and expanded cohort screening, we identified a novel genetic substrate p.Arg518Cys/His-CACNA1C, in patients with a complex phenotype including LQTS, HCM, and CHDs annotated as cardiac-only Timothy syndrome. Our electrophysiological studies, identification of mutations at the same amino acid position in multiple pedigrees, and co-segregation with disease in these pedigrees provides evidence that p.Arg518Cys/His is the pathogenic substrate for the observed phenotype.

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“…On autopsy examination, many different causes of SD can be identified. [ 18 ] The most common cause of SD is SCD, defined as death from a cardiac cause occurring shortly after the onset of symptoms. [ 6 ] Many cases of SCD have identifiable abnormalities such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, coronary artery anomalies or myocarditis.…”

Section: Sudden Unexplained Death and Channelopathiesmentioning

confidence: 99%

“…[ 6 ] Many cases of SCD have identifiable abnormalities such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, coronary artery anomalies or myocarditis. [ 18 ] However, a significant proportion of SD (3-53%) has no identifiable cause on autopsy examination, and these are labeled SUD. [ 18 ] SUD occurs at about 33/million people/year.…”

Section: Sudden Unexplained Death and Channelopathiesmentioning

confidence: 99%

“…[ 18 ] However, a significant proportion of SD (3-53%) has no identifiable cause on autopsy examination, and these are labeled SUD. [ 18 ] SUD occurs at about 33/million people/year. [ 19 ] SUD of young persons is a rare occurrence, best studied in the developed world, with an incidence of 1.3-8.5/100,000 patient years.…”

Section: Sudden Unexplained Death and Channelopathiesmentioning

confidence: 99%

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Inherited arrhythmias: The cardiac channelopathies

Behere

Weindling

2015

Ann Pediatr Card

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Ion channels in the myocardial cellular membrane are responsible for allowing the cardiac action potential. Genetic abnormalities in these channels can predispose to life-threatening arrhythmias. We discuss the basic science of the cardiac action potential; outline the different clinical entities, including information regarding overlapping diagnoses, touching upon relevant genetics, new innovations in screening, diagnosis, risk stratification, and management. The special considerations of sudden unexplained death and sudden infant death syndrome are discussed. Scientists and clinicians continue to reconcile the rapidly growing body of knowledge regarding the molecular mechanisms and genetics while continuing to improve our understanding of the various clinical entities and their diagnosis and management in clinical setting. Two separate searches were run on the National Center for Biotechnology Information's website. The first using the term cardiac channelopathies was run on the PubMed database using filters for time (published in past 5 years) and age (birth-18 years), yielding 47 results. The second search using the medical subject headings (MeSH) database with the search terms “Long QT Syndrome” (MeSH) and “Short QT Syndrome” (MeSH) and “Brugada Syndrome” (MeSH) and “Catecholaminergic Polymorphic Ventricular Tachycardia” (MeSH), applying the same filters yielded 467 results. The abstracts of these articles were studied, and the articles were categorized and organized. Articles of relevance were read in full. As and where applicable, relevant references and citations from the primary articles where further explored and read in full.

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The molecular autopsy: an indispensable step following sudden cardiac death in the young?

Cited by 31 publications

References 40 publications

Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances

Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances

Identification and Functional Characterization of a Novel CACNA1C -Mediated Cardiac Disorder Characterized by Prolonged QT Intervals With Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death

Inherited arrhythmias: The cardiac channelopathies

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