Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

Purpose: Germ-line testing for panels of cancer genes using next-generation sequencing is becoming more common in clinical care. We report our experience as a clinical laboratory testing both well-established, high-risk cancer genes (e.g.

Torsades de pointes following acute myocardial infarction: evidence for a deadly link with a common genetic variant.

Background: Although QT prolongation following myocardial infarction (MI) is generally moderate, cases with marked QT prolongation leading to life-threatening torsades de pointes (TdP) have been described.

Objective: To investigate the genetic substrate of this phenomenon.

Methods: We studied 13 patients who developed TdP in the subacute phase of MI (2-11 days) and a group of 133 ethnically matched controls with uncomplicated MI.

Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise.

Objectives: The aims of this study were to determine the spectrum and prevalence of "background genetic noise" in the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) genetic test and to determine genetic associations that can guide the interpretation of a positive test result.

Background: ARVC is a potentially lethal genetic cardiovascular disorder characterized by myocyte loss and fibrofatty tissue replacement of the right ventricle. Genetic variation among the ARVC susceptibility genes has not been systematically examined, and little is known about the background noise associated with the ARVC genetic test.

Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death.

Background: L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death.

Objective: The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Ca(v)1.

An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.

Background: Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype.

Objective: This study sought to perform a retrospective analysis of BrS databases from 9 centers that have each genotyped >100 unrelated cases of suspected BrS.

A mutation in the beta 3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype.

Background: Brugada syndrome, characterized by ST-segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in 6 different genes. We identify and characterize a mutation in a new gene.

Methods And Results: A 64-year-old white male displayed a type 1 ST-segment elevation in V1 and V2 during procainamide challenge.

Dual variation in SCN5A and CACNB2b underlies the development of cardiac conduction disease without Brugada syndrome.

Background: Inherited loss of function mutations in SCN5A have been linked to overlapping syndromes including cardiac conduction disease and Brugada syndrome (BrS). The mechanisms responsible for the development of one without the other are poorly understood.

Methods: Direct sequencing was performed in a family with cardiac conduction disease.

Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.

Background: Long QT syndrome (LQTS) is a potentially lethal, highly treatable cardiac channelopathy for which genetic testing has matured from discovery to translation and now clinical implementation.

Objectives: Here we examine the spectrum and prevalence of mutations found in the first 2,500 unrelated cases referred for the FAMILION LQTS clinical genetic test.

Methods: Retrospective analysis of the first 2,500 cases (1,515 female patients, average age at testing 23 +/- 17 years, range 0 to 90 years) scanned for mutations in 5 of the LQTS-susceptibility genes: KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6).

SCN5A mutation associated with acute myocardial infarction.

Ventricular tachycardia and fibrillation (VT/VF) complicating Brugada syndrome, a genetic disorder linked to SCN5A mutations, and VF complicating acute myocardial infarction (AMI) have both been linked to phase 2 reentry. Because of these mechanistic similarities in arrhythmogenesis, we examined the contribution of SCN5A mutations to VT/VF complicating AMI. Nineteen consecutive patients developing VF during AMI were enrolled.

Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome.

Introduction: The Brugada Syndrome (BrS), an inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in four different genes leading to a loss of function in sodium and calcium channel activity. Although the transient outward current (I(to)) is thought to play a prominent role in the expression of the syndrome, mutations in I(to)-related genes have not been identified as yet.

Methods And Results: One hundred and five probands with BrS were screened for ion channel gene mutations using single strand conformation polymorphism (SSCP) electrophoresis and direct sequencing.

Gain of function in IKs secondary to a mutation in KCNE5 associated with atrial fibrillation.

Background: Atrial fibrillation (AF) is the most common clinical arrhythmia and a major cause of cardiovascular morbidity and mortality. Among the gene defects previously associated with AF is a gain of function of the slowly activating delayed rectifier potassium current IKs, secondary to mutations in KCNQ1. Coexpression of KCNE5, the gene encoding the MiRP4 beta-subunit, has been shown to reduce IKs.

Genetic predisposition and cellular basis for ischemia-induced ST-segment changes and arrhythmias.

Recent reports have highlighted the importance of a family history of sudden death as a risk for ventricular fibrillation (VF) in patients experiencing acute myocardial infarction (AMI), pointing to the possibility of a genetic predisposition. This report briefly reviews 2 recent studies designed to examine the hypothesis that there is a genetic predisposition to the development of arrhythmias associated with AMI. Ventricular tachycardia and VF (VT/VF) complicating AMI as well as arrhythmias associated with Brugada syndrome, a genetic disorder linked to SCN5A mutations, have both been linked to phase 2 reentry.

Novel mutation in the SCN5A gene associated with arrhythmic storm development during acute myocardial infarction.

Background: Ventricular tachycardia (VT) and ventricular fibrillation (VF) complicating Brugada syndrome, a genetic disorder linked to SCN5A mutations, and VF complicating acute myocardial infarction (AMI) both have been linked to phase 2 reentry.

Objective: Given the mechanistic similarities in arrhythmogenesis, the purpose of this study was to examine the contribution of SCN5A mutations to VT/VF complicating AMI.

Methods: Nineteen consecutive patients developing VF during AMI were enrolled in the study.

Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.

Background: Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death.

Methods And Results: Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing.

Functional expression of "cardiac-type" Nav1.5 sodium channel in canine intracardiac ganglia.

Background: The autonomic nervous system has been implicated in several arrhythmogenic diseases, including long QT syndrome type 3 (LQT3) and Brugada syndrome. Scarce information on the cellular components of the intrinsic cardiac ganglia from higher mammals has limited our understanding of the role of the autonomic nervous system in such diseases.

Objectives: The purpose of this study was to isolate and characterize the electrophysiologic properties of canine intracardiac neurons.

The homeodomain transcription factor Irx5 establishes the mouse cardiac ventricular repolarization gradient.

Rhythmic cardiac contractions depend on the organized propagation of depolarizing and repolarizing wavefronts. Repolarization is spatially heterogeneous and depends largely on gradients of potassium currents. Gradient disruption in heart disease may underlie susceptibility to fatal arrhythmias, but it is not known how this gradient is established.

Provocation of sudden heart rate oscillation with adenosine exposes abnormal QT responses in patients with long QT syndrome: a bedside test for diagnosing long QT syndrome.

Aims: As arrhythmias in the long QT syndrome (LQTS) are triggered by heart rate deceleration or acceleration, we speculated that the sudden bradycardia and subsequent tachycardia that follow adenosine injection would unravel QT changes of diagnostic value in patients with LQTS.

Methods And Results: Patients (18 LQTS and 20 controls) received intravenous adenosine during sinus rhythm. Adenosine was injected at incremental doses until atrioventricular block or sinus pauses lasting 3 s occurred.

Cryptic 5' splice site activation in SCN5A associated with Brugada syndrome.

The Brugada syndrome (BS) is characterized by ST segment elevation in the right precordial leads and sudden cardiac death. The disease is linked to mutations in SCN5A in approximately 20% of cases. We collected a large family with BS and have identified a novel intronic mutation.

Value of electrocardiographic parameters and ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations.

Background: The Brugada syndrome is an arrhythmogenic disease caused in part by mutations in the cardiac sodium channel gene, SCN5A. The electrocardiographic pattern characteristic of the syndrome is dynamic and is often absent in affected individuals. Sodium channel blockers are effective in unmasking carriers of the disease.

Gene expression analysis in the hippocampal formation of tree shrews chronically treated with cortisol.

Adrenal corticosteroids influence the function of the hippocampus, the brain structure in which the highest expression of glucocorticoid receptors is found. Chronic high levels of cortisol elicited by stress or through exogenous administration can cause irreversible damage and cognitive deficits. In this study, we searched for genes expressed in the hippocampal formation after chronic cortisol treatment in male tree shrews.

Identification of genes regulated by chronic psychosocial stress and antidepressant treatment in the hippocampus.

Analysis of differentially expressed genes in the brain is a promising tool for elucidating pathological mechanisms that lead to central nervous disorders. Stress is known to be involved in the development of psychopathologies such as depression. In the present study, we searched for differentially expressed genes in the hippocampal formation after chronic psychosocial stress and after treatment with the antidepressant clomipramine.

Sudden death associated with short-QT syndrome linked to mutations in HERG.

Background: Sudden cardiac death takes the lives of more than 300 000 Americans annually. Malignant ventricular arrhythmias occurring in individuals with structurally normal hearts account for a subgroup of these sudden deaths. The present study describes the genetic basis for a new clinical entity characterized by sudden death and short-QT intervals in the ECG.

Differential regulation of polysialyltransferase expression during hippocampus development: Implications for neuronal survival.

Polysialyltransferases ST8SiaII/STX and ST8SiaIV/PST add polysialic acid (PSA) to the neural cell adhesion molecule (NCAM). Surface-located PSA is involved in cell-cell interactions participating in structural and functional plasticity of neuronal circuits. This study was undertaken to investigate the polysialyltransferase regulation pattern during hippocampal development.

Analysis of gene expression in the rat hippocampus using Real Time PCR reveals high inter-individual variation in mRNA expression levels.

In mammals, gene transcription is a step subjected to tight regulation mechanisms. In fact, changes in mRNA levels in the central nervous system (CNS) can account for numerous phenotypic differences in brain function. We performed a high-resolution analysis of mRNA expression levels for 37 genes selected from a normal rat hippocampus cDNA library.

Trypanosoma cruzi surface mucins with exposed variant epitopes.

The protozoan parasite Trypanosoma cruzi, the agent of Chagas disease, has a large number of mucin molecules on its surface, whose expression is regulated during the life cycle. These mucins are the main acceptors of sialic acid, a monosaccharide that is required by the parasite to infect and survive in the mammalian host. A large mucin-like gene family named TcMUC containing about 500 members has been identified previously in T.