Anna Iglesias

Genetics and cardiac channelopathies.

Abstract: Sudden cardiac death is a major contributor to mortality in industrialized nations; in fact, it is the cause of more deaths than acquired immune deficiency syndrome, lung and breast cancer, and stroke together. Frequently, the autopsy becomes the principal diagnostic tool because macroscopic and microscopic analyses reveal the underlying cause of death. However, a significant number of sudden cardiac deaths remain unexplained. These cases are referred to as “natural” or arrhythmogenic. In the young, in up to 50% of sudden cardiac death cases, sudden death is the first and only clinical manifestation of an inherited cardiac disease that had remained undetected by conventional clinical investigations. To improve diagnosis, genetic testing has recently been added to these clinical tools. During the last two decades, there has been considerable progress in the understanding about genetics of sudden cardiac death. With that new information, the probands and their family members can make an informed decision regarding their care and know whether and to what extent they are at risk of suffering from the disease. Thus, genetic technology and expertise have become essential for the diagnosis of some forms of inherited cardiac diseases and to provide a basis for subsequent prevention strategies. This review focuses on recent advances in the understanding of cardiopathies owing to genetic investigations.

A Missense Mutation in the Sodium Channel β2 Subunit Reveals SCN2B as a New Candidate Gene for Brugada Syndrome

Brugada Syndrome (BrS) is a familial disease associated with sudden cardiac death. A 20%–25% of BrS patients carry genetic defects that cause loss‐of‐function of the voltage‐gated cardiac sodium channel. Thus, 70%–75% of patients remain without a genetic diagnosis. In this work, we identified a novel missense mutation (p.Asp211Gly) in the sodium β2 subunit encoded by SCN2B, in a woman diagnosed with BrS. We studied the sodium current (INa) from cells coexpressing Nav1.5 and wild‐type (β2WT) or mutant (β2D211G) β2 subunits. Our electrophysiological analysis showed a 39.4% reduction in INa density when Nav1.5 was coexpressed with the β2D211G. Single channel analysis showed that the mutation did not affect the Nav1.5 unitary channel conductance. Instead, protein membrane detection experiments suggested that β2D211G decreases Nav1.5 cell surface expression. The effect of the mutant β2 subunit on the INa strongly suggests that SCN2B is a new candidate gene associated with BrS.

Coexistence of epilepsy and Brugada syndrome in a family with SCN5A mutation

Cardiac arrhythmias are associated with abnormal channel function due to mutations in ion channel genes. Epilepsy is a disorder of neuronal function also involving abnormal channel function. It is increasingly demonstrated that the etiologies of long QT syndrome and epilepsy may partly overlap. However, only a few genetic studies have addressed a possible link between cardiac and neural channelopathies. We describe a family showing the association between Brugada syndrome and epilepsy in which a known mutation in the SCN5A gene (p.W1095X, c.3284G>A) was identified. We suggest that this mutation can be responsible for cardiac and brain involvement, probably at different developmental age in the same individual. This observation confirms the possibility that SCN5A mutations may confer susceptibility for recurrent seizure activity, supporting the emerging concept of a genetically determined cardiocerebral channelopathy.

Increase in sudden death from coronary artery disease in young adults

BACKGROUND Sudden cardiac death (SCD) is the most common cause of death in adults aged <65 years, making it a major public health problem. A growing incidence in coronary artery disease (CAD) in young individuals has been predicted in developed countries, which could in turn be associated with an increase in SCD in this population. The aim of the study was to assess the prevalence of CAD among autopsies of young individuals (<40 years) who had sudden death (SD). METHODS We selected all the autopsies referred to the Montreal Heart Institute and Maisonneuve-Rosemont Hospital from January 2002 to December 2006 that corresponded to individuals <40 years old who had died suddenly. For each decedent, the following data were collected: cause of death, autopsy findings, available clinical history, toxicological findings, and cardiovascular risk factors. RESULTS From a total of 1,260 autopsies, 243 fulfilled the inclusion criteria. Coronary artery disease was the main cause of SCD from age 20 years, representing the 37% of deaths in the group of 21 to 30 years old, and up to 80% of deaths in the group of 31 to 40 years old. Among individuals who died of CAD, 3-vessel disease was observed in 39.7% of cases. Moreover, among the whole population <40 years old, at least 1 significant coronary lesion was observed in 39.5% of cases, irrespective to the cause of death. In the multivariable analysis, an increased BMI (hazard ratio 1.1 for each kg/m(2), 95% CI 1.01-1.1) and hypercholesterolemia (hazard ratio 2.4, 95% CI 1.7-333.3) showed to be the modifiable factors related to an increased risk of SD from CAD. CONCLUSIONS In our population, CAD was the main cause of SD from age 20 years. These data bring into question whether present prevention strategies are sufficient and reinforce the need to extend prevention to younger ages.

Genetics of arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is a rare clinical entity characterised by fibro-fatty replacement of myocardium, mainly involving right ventricular free wall, leading to malignant electrical instability and sudden cardiac death. The disease is inherited in up to 50% of cases, with incomplete penetrance and variable phenotypic expression. To date, more than 300 pathogenic mutations have been identified in 12 genes, mainly with autosomal dominant inheritance. Here, we focus on recent advances in the genetics of arrhythmogenic right ventricular cardiomyopathy. Despite continuous improvements, current genotype–phenotype studies have not contributed yet to establish a genetic risk stratification of the disease.

Negative autopsy and sudden cardiac death.

Forensic medicine defines the unexplained sudden death as a death with a non-conclusive diagnosis after autopsy. Molecular diagnosis is being progressively incorporated in forensics, mainly due to improvement in genetics. New genetic technologies may help to identify the genetic cause of death, despite clinical interpretation of genetic data remains the current challenge. The identification of an inheritable defect responsible for arrhythmogenic syndromes could help to adopt preventive measures in family members, many of them asymptomatic but at risk of sudden death. This multidisciplinary translational research requires a specialized team.

Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia

Barahona‐Dussault C, Benito B, Campuzano O, Iglesias A, Leung TL, Robb L, Talajic M, Brugada R. Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Genetics of Brugada syndrome.

Purpose of review The Brugada syndrome has been investigated in depth since its description in 1992 both on a clinical and on a basic research level. Since the discovery of the first genetic defect in 1998, several genes have been subsequently identified. However, to date all these genes together explain only 30% of the cases, indicating that there is still an important amount of work to be done to totally unravel the genetic basis of this lethal disease. In the present study, we will focus on recent achievements in the genetic basis of this disease. Recent findings In 2009, several additional genetic mutations have been associated with the disease. Additionally, a common variant has been described as a genetic modulator of Brugada syndrome among carriers of a SCN5A mutation. Summary The number of scientific publications dealing with the syndrome has continued to increase substantially in recent years. New polymorphisms, mutations and genes associated with the disease have been described. However, despite the advances, knowledge of the genetic determinants of the Brugada syndrome remains limited.

Determining the Pathogenicity of Genetic Variants Associated with Cardiac Channelopathies

Advancements in genetic screening have generated massive amounts of data on genetic variation; however, a lack of clear pathogenic stratification has left most variants classified as being of unknown significance. This is a critical limitation for translating genetic data into clinical practice. Genetic screening is currently recommended in the guidelines for diagnosis and treatment of cardiac channelopathies, which are major contributors to sudden cardiac death in young people. We propose to characterize the pathogenicity of genetic variants associated with cardiac channelopathies using a stratified scoring system. The development of this system was considered by using all of the tools currently available to define pathogenicity. The use of this scoring system could help clinicians to understand the limitations of genetic associations with a disease, and help them better define the role that genetics can have in their clinical routine.

Genetic Basis of Dilated Cardiomyopathy

Dilated cardiomyopathy is a rare cardiac disease characterized by left ventricular dilatation and systolic dysfunction leading to heart failure and sudden cardiac death. Currently, despite several conditions have been reported as aetiologies of the disease, a large number of cases remain classified as idiopathic. Recent studies determine that nearly 60% of cases are inherited, therefore due to a genetic cause. Progressive technological advances in genetic analysis have identified over 60 genes associated with this entity, being TTN the main gene, so far. All these genes encode a wide variety of myocyte proteins, mainly sarcomeric and desmosomal, but physiopathologic pathways are not yet completely unraveled. We review the recent published data about genetics of familial dilated cardiomyopathy.