Selective acquired long QT syndrome (saLQTS) upon risperidone treatment

Numerous structurally unrelated drugs, including antipsychotics, can prolong QT interval and trigger the acquired long QT syndrome (aLQTS). All of them are thought to act at the level of KCNH2, a subunit of the potassium channel. Although the QT-prolonging drugs are proscribed in the subjects with aLQTS, the individual response to diverse QT-prolonging drugs may vary substantially

A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families

Background. - Mutations in the gene encoding the human cardiac sodium channel (SCN5A) have been associated with three distinct cardiac arrhythmia disorders: the long QT syndrome, the Brugada syndrome and cardiac conduction disease. Here we report the biophysical features of a novel sodium channel mutation, E161K, which we identified in individuals of two non-related families with symptoms of bradycardia. sinus node dysfunction, generalized conduction disease and Brugada syndrome, or combinations thereof. Methods and results. - Wild-type (WT) or E 161 K sodium channel alpha-subunit and beta-subunit were cotransfected into tsA201 cells to study the functional consequences of mutant sodium channels. Characterization of whole-cell sodium current (IN.) using the whole cell patch-clamp technique revealed that the E 16 1 K mutation caused an almost threefold reduction in current density (P <0.001), and an 11.9 mV positive shift of the voltage-dependence of activation (P <0.0001). The inactivation properties of mutant and WT sodium channels were similar. These results suggest an overall reduction of E161 I-Na. Incorporation of the experimental findings into computational models demonstrate atrial and ventricular conduction slowing as well as a reduction in sinus rate by slowing of the diastolic depolarization rate and upstroke velocity of the sinus node action potential. This reduction in sinus rate was aggravated by application of acetylcholine, simulating the dominant vagal tone during night. Conclusion. - Our experimental and computational analysis of the E161K mutation suggests that a loss of sodium channel function is not only associated with Brugada syndrome and conduction disease, but may also cause sinus node dysfunction in carriers of this mutation. (c) 2005 Elsevier Ltd. All rights reserve

Recommendations for genetic testing and counselling after sudden cardiac death: practical aspects for Swiss practice

There is a need to standardise, within a coordinated Swiss framework, the practical aspects of genetic testing and genetic counselling on possibly inherited cardiovascular disorders in relatives of a sudden cardiac death (SCD) victim. Because of the major advances in genetic investigation techniques and recent publication of international guidelines in the field of cardiology, genetics and pathology, we consider it important to summarise the current evidence and propose an optimal approach to post-mortem genetic investigation for SCD victims and their families in Switzerland. In this article, we discuss important technical, financial and medico-ethical aspects, and provide updated information on specific situations in which forensic pathologists, general practitioners and cardiologists should suspect a genetic origin of the SCD. At present, the principles of benefit, the duty to warn and the impact of genetic information for family members at risk are considered as strong justifications for post-mortem disclosure and prevail over the arguments of respect for a deceased person's privacy and confidentiality. This paper underlines also the need to update and improve the general knowledge concerning the genetic risk of cardiovascular pathologies, the importance to perform an autopsy and post-mortem genetic testing in SCD victims, and to develop standardized post-mortem disclosure policy at national and international levels for SCD cases and relatives

Distinguishing Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia-Associated Mutations From Background Genetic Noise

ObjectivesThe 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.BackgroundARVC 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.MethodsUsing direct deoxyribonucleic acid sequencing, the coding exons/splice junctions of PKP2, DSP, DSG2, DSC2, and TMEM43 were genotyped for 93 probands diagnosed with ARVC from the Netherlands and 427 ostensibly healthy controls of various ethnicities. Eighty-two additional ARVC cases were obtained from published reports, and additional mutations were included from the ARVD/C Genetic Variants Database.ResultsThe overall yield of mutations among ARVC cases was 58% versus 16% in controls. Radical mutations were hosted by 0.5% of control individuals versus 43% of ARVC cases, while 16% of controls hosted missense mutations versus a similar 21% of ARVC cases. Relative to controls, mutations in cases occurred more frequently in non-Caucasians, localized to the N-terminal regions of DSP and DSG2, and localized to highly conserved residues within PKP2 and DSG2.ConclusionsThis study is the first to comprehensively evaluate genetic variation in healthy controls for the ARVC susceptibility genes. Radical mutations are high-probability ARVC-associated mutations, whereas rare missense mutations should be interpreted in the context of race and ethnicity, mutation location, and sequence conservation

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. Methods Using direct deoxyribonucleic acid sequencing, the coding exons/splice junctions of PKP2, DSP, DSG2, DSC2, and TMEM43 were genotyped for 93 probands diagnosed with ARVC from the Netherlands and 427 ostensibly healthy controls of various ethnicities. Eighty-two additional ARVC cases were obtained from published reports, and additional mutations were included from the ARVD/C Genetic Variants Database. Results The overall yield of mutations among ARVC cases was 58% versus 16% in controls. Radical mutations were hosted by 0.5% of control individuals versus 43% of ARVC cases, while 16% of controls hosted missense mutations versus a similar 21% of ARVC cases. Relative to controls, mutations in cases occurred more frequently in non-Caucasians, localized to the N-terminal regions of DSP and DSG2, and localized to highly conserved residues within PKP2 and DSG2. Conclusions This study is the first to comprehensively evaluate genetic variation in healthy controls for the ARVC susceptibility genes. Radical mutations are high-probability ARVC-associated mutations, whereas rare missense mutations should be interpreted in the context of race and ethnicity, mutation location, and sequence conservation. (J Am Coll Cardiol 2011;57:2317-27) (C) 2011 by the American College of Cardiology Foundatio

Comprehensive dna analysis in dutch ARVD/C patients

Introduction: Familial Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is an autosomal dominantly inherited disease with incomplete penetrance and highly variable expression. Mutations in genes encoding 5 desmosomal proteins and TMEM43 usually underlie ARVD/C. Aim: Comprehensive sequencing of all 6 genes in a large cohort of Dutch ARVD/C patients (pts) correlated with phenotypic characteristics. Methods: Inclusion of 109 ARVD/C pts (81 men, age 49±14 yrs) according to diagnostic Task Force Criteria (TFC). Clinical history and data on separate TFC were collected. DNA of all 109 pts was directly sequenced for mutations in desmosomal genes PKP2, DSC2, DSG2, DSP and JUP. In 81 cases TMEM43 was also analyzed. Pathogenic mutations were defined as DNA sequence variations disrupting conserved residues and not present in 200 ethnically-matched controls. Clinical characteristics were related to specific genes, type (truncating or not) and number of mutations. Results: In 63 of 109 pts (58%) single mutations were observed: 19 different PKP2 mutations in 57 cases, 5 in DSG2 and 1 in DSC2. Five more pts carried 2 mutations: in PKP2 and additionally in DSG2 (n=2), DSP (n=2) or TMEM43 (n=1). Mutations occurred equally in men and women. Phenotype variations were not related to gene or type of mutations. First arrhythmic event was at significantly younger age in pts with mutation than those without, and youngest in those 5 pts with bigenic involvement (mean age for 0, 1 and 2 mutations: 43, 34 and 21 yrs, resp). Also, between groups with 0, 1 and 2 mutations, occurrence of negative T waves in leads V1-3 (41, 80 and 100%, resp) and major structural abnormalities (46, 65 and 100% resp) was significantly different. Frequency of all other parameters was similar. Conclusions: In 68 of 109 (62%) Dutch ARVD/C patients pathogenic mutations were observed, mainly in PKP2, with multiple mutations in 5 cases. Mutation carriers more often had negative T waves in V1-3 and structural abnormalities. Moreover, they presented at younger age than patients without mutations; this age was even younger when multiple genes were affected. Screening of all relevant genes is needed for appropriate genotype-phenotype correlation

Genotype-phenotype analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy:Follow-up of a large series of dutch index-patients and family members

Background: In Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) causative mutations in genes encoding 5 desmosomal proteins or TMEM43 are found in the majority of patients. One of the primary clinical challenges in ARVD/C is timely diagnosis of those still asymptomatic. However, previous studies mainly involved overt ARVD/C index-patients. Follow-up data on relatives are scarce. Therefore, we sequenced all 6 genes in a large cohort of ARVD/C families and correlated results with clinical follow-up. Methods: 149 ARVD/C index-patients (111 men, age 49±13 years) according to 2010 Task Force Criteria (TFC) and 302 family members from 93 different families (282 asymptomatic, 135 men, age 44±13 years) were clinically and genetically analyzed. DNA analysis comprised sequencing of PKP2, DSC2, DSG2, DSP, JUP and TMEM43 and multiple ligation-dependent probe amplification (MLPA) to identify large PKP2 deletions. Results: Pathogenic mutations were found in 87 of 149 index-patients (58%): 90% PKP2 and multiple mutations in 4 cases. MLPA revealed 3 large PKP2 deletions (2%). Mutation carriers presented at younger age than non-carriers (35±12 vs 40±14 years; p=0.042). Familial cases were identified in 42 of 93 (45%) of index-patients with relatives screened: 90% with mutations. In total, 57 of 282 asymptomatic relatives (20%) showed signs of ARVD/C (age 47±18 years, 48 with mutations). See table 2. Terminal activation duration (TAD) 7ge;55ms occurred more than negative T waves in V1-3 (12 vs 7%), especially in those age

Arrhythmogenic right ventricular dysplasia/cardiomyopathy: Pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study

Background-: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. Methods and Results-: One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V1 to V3, especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations). Conclusions-: Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives