Search

Background A pathogenic variant in the gene encoding phospholamban (PLN; p.Arg14del) may cause cardiomyopathy, the pathophysiologic hallmark of which is cardiac fibrosis that may cause malignant ventricular arrhythmias and severe heart failure. There is no evidence-based therapy to modify disease progression in presymptomatic pathogenic variant carriers. Eplerenone is a selective mineralocorticoid receptor antagonist with established antifibrotic properties, and may be a potentially interesting treatment in PLN p.Arg14del mutation carriers. Purpose To investigate if preventive therapy with eplerenone attenuates disease onset and progression in PLN cardiomyopathy. Methods 84 presymptomatic PLN p.Arg14del mutation carriers (median age 39 [27–50] years, 44% males) were randomized 1:1 to receive eplerenone (50mg once daily) or no treatment, and endpoints were adjudicated in a blinded fashion (PROBE design). Baseline values were acquired including demographics, cardiac magnetic resonance imaging (CMR) parameters (ventricular volumes, systolic function, late gadolinium enhancement (LGE)), and electrocardiographic parameters (QRS voltages and ventricular ectopy per 24 hour). Subjects were re-evaluated every year and CMR was performed at baseline and after three years. The composite endpoint included LVEDV/RVEDV increase (>10%), LVEF/RVEF decrease (5%), newly developed LGE on CMR, increase in ventricular ectopy (>100% PVCs/24h if >1000 PVCs/24h), decrease in QRS voltage (>25%), non-sustained ventricular tachycardia, symptoms or arrhythmias necessitating treatment, and cardiovascular death. Results Two out of 84 subjects (2%) were lost to follow up. 49 out of 82 remaining subjects (60%) reached the composite end point, 25 (60%) in the control group, 24 (60%) in the treatment group (p=0.825). There was no significant difference between the groups when considering the individual end points, see Table 1. Baseline and follow up CMR was performed on 76 subjects, 39 in the control group, 37 in the treatment group. In total there were 10 (13%) cases of newly developed LGE, 6 (18%) in the control group, 4 (12%) in the treatment group (p=0.556), see Figure 1. Conclusions Eplerenone did not significantly attenuate disease onset and progression in presymptomatic PLN p.Arg14del mutation carriers. There was no significant difference in new incidence of LGE between the treatment and control groups. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was financially supported by the Netherlands Cardiovascular Research Initiative, an initiative supported by the Dutch Heart Foundation (The Hague, Netherlands).

Background/Introduction Recently, a variant-specific prediction model for PLN p.Arg14del variant carriers was developed to predict individual malignant ventricular arrhythmia (VA) risk to inform decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts malignant VA risk from data at diagnosis, but iterative evaluation of malignant VA risk may be warranted considering that the risk factors for malignant VA are progressive. Purpose To evaluate the diagnostic performance of the PLN p.Arg14del risk model. Methods/Results Date were collected of 278 PLN p.Arg14del variant carriers at 3 year follow-up. This was considered the new baseline for the survival analysis. Patients with history of malignant VA at both baseline and during the first 3 years after baseline were excluded. At 3 year patients were aged 40.1±18.0 year and 40.7% was male. Median left ventricular ejection fraction (LVEF) was 53% and percentage with microvoltages was 10.3. During a median follow-up of 4 years (Interquartile range 1.8–6.5) 31 (11%) carriers experienced malignant VA, defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. Reevaluation of the predictors with the 3 year follow-up data revealed hazard rates that were similar to those in the original PLN p.Arg14del risk model; LVEF per 1% decrease (hazard ratio (HR) 1.10 [95% confidence interval (CI), 1.06–1.12]; p Conclusion The PLN p.Arg14del risk model is valid at 3 year follow-up in PLN p.Arg14del variant carriers with no history of malignant VA and can therefore be used to inform decision-making for primary prevention ICD implantation not merely at diagnosis, but also during follow-up and can be seen as a type of validation in a cohort where no other large cohort is present to perform external validation. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): 1. PSIDER: From pluripotent stem cells to prime editing gene therapy for inheritedcardiomyopathies. ZOn-MW.2. PREDICT2: Predicting sudden cardiac arrest. The Dutch Heart Foundation.

Background Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by truncating variants in the MYBPC3 gene. HCM is an important cause of sudden cardiac death; however, overall prognosis is good and penetrance in genotype-positive individuals is incomplete. The underlying mechanisms are poorly understood and risk stratification remains limited. Aim To create a nationwide cohort of carriers of truncating MYBPC3 variants for identification of predictive biomarkers for HCM development and progression. Methods In the multicentre, observational BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort, carriers of the c.2373dupG, c.2827C > T, c.2864_2865delCT and c.3776delA MYBPC3 variants are included and prospectively undergo longitudinal blood collection. Clinical data are collected from first presentation onwards. The primary outcome constitutes a composite endpoint of HCM progression (maximum wall thickness ≥ 20 mm, septal reduction therapy, heart failure occurrence, sustained ventricular arrhythmia and sudden cardiac death). Results So far, 250 subjects (median age 54.9 years (interquartile range 43.3, 66.6), 54.8% male) have been included. HCM was diagnosed in 169 subjects and dilated cardiomyopathy in 4. The primary outcome was met in 115 subjects. Blood samples were collected from 131 subjects. Conclusion BIO FOr CARe is a genetically homogeneous, phenotypically heterogeneous cohort incorporating a clinical data registry and longitudinal blood collection. This provides a unique opportunity to study biomarkers for HCM development and prognosis. The established infrastructure can be extended to study other genetic variants. Other centres are invited to join our consortium.

Background The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. Aims The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. Methods iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. Baseline results A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and Conclusion iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856).

In relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy, early detection of disease onset is essential to prevent sudden cardiac death and facilitate early treatment of heart failure. However, the optimal screening interval and combination of diagnostic techniques are unknown. The clinical course of disease in index patients and their relatives is variable due to incomplete and age-dependent penetrance. Several biomarkers, electrocardiographic and imaging (echocardiographic deformation imaging and cardiac magnetic resonance imaging) techniques are promising non-invasive methods for detection of subclinical cardiomyopathy. However, these techniques need optimisation and integration into clinical practice. Furthermore, determining the optimal interval and intensity of cascade screening may require a personalised approach. To address this, the CVON-eDETECT (early detection of disease in cardiomyopathy mutation carriers) consortium aims to integrate electronic health record data from long-term follow-up, diagnostic data sets, tissue and plasma samples in a multidisciplinary biobank environment to provide personalised risk stratification for heart failure and sudden cardiac death. Adequate risk stratification may lead to personalised screening, treatment and optimal timing of implantable cardioverter defibrillator implantation. In this article, we describe non-invasive diagnostic techniques used for detection of subclinical disease in relatives of index patients with dilated cardiomyopathy and arrhythmogenic cardiomyopathy.

Background Mutations in TGFB3 cause Loeys-Dietz syndrome-5 (LDS5), an autosomal dominantly inherited connective tissue disorder. LDS5 is characterized by aortic aneurysms and dissections associated with systemic features mainly involving the ocular and skeletal systems. Precise delineation of LDS5 phenotype is difficult because of the small number of identified cases. Purpose The purpose of this study was to further define LDS5 with an emphasis on cardiologic features by describing the genotype and phenotype in an international cohort of patients. Methods We performed a retrospective cross-sectional multicentre study. Genetic testing was performed as a part of standard medical care. Clinical data were collected by means of an anonymized questionnaire, which was sent to the referent physicians. Results Ten (7 novel) TGFB3 mutations were identified in 31 patients (16 index patients). The mean age at last evaluation was 32 years (range 4–60 years). Aortic root dilatation, varices, and mitral valve insufficiency were the most common cardiovascular findings, reported in 28%, 22%, and 21% of patients, respectively. Higher incidences (40%, 29%, and 25%) of these findings were observed in the index patients. Four patients (8%) underwent aortic surgery, all after age 40. Abdominal aortic aneurysms were reported in 2/26 (8%) patients. Extra aortic artery disease included iliac artery aneurysm (one index patient) and tortuosity of the internal carotid and vertebral arteries (one index patient and one relative). The most frequently reported systemic features were high-arched palate, arachnodactyly, pes planus, pectus deformity, and joint hypermobility. Interestingly, we identified an homozygous TGFB3 mutation in a patient who presented with aortic dilatation at age 17, splenic torsion, severe myopia, cleft palate, and other skeletal features. Her heterozygous parents, brother, and sister displayed signs of the disease, but to a milder degree. To the best of our knowledge, this is the first identification of homozygous TGFB3 mutation. Conclusions Our data are in line with previous research, showing that aortic root dilatation is the main cardiovascular feature of LDS5. No deaths related to cardiovascular events were reported in any of the presented families. The cardiovascular phenotype of LDS5 appears to be milder compared to other vascular connective tissue disorder, such as Marfan syndrome, although our findings suggest that homozygosity is associated with a more severe and early-onset phenotype.

Background/Introduction The founder mutation p.Arg14del in the gene encoding phospholamban (PLN) is a known cause of arrhythmogenic cardiomyopathy (ACM) with distinct clinical features, such as microvoltages on the ECG and right or left ventricular dysfunction or both. At present, risk stratification for ICD implantation in carriers of this mutation is based on left ventricular ejection fraction and previous ventricular arrhythmia's, which are not specific risk factors for the PLN p.Arg14del cardiomyopathy. Purpose Our goal is to develop a mutation specific prediction model for incident malignant ventricular arrhythmia to guide ICD implantation. Methods Data were collected from p.Arg14del carriers with no history of malignant VA at baseline, identified between September 2009 and June 2018 in three Dutch university hospitals. Genetic analysis of PLN was performed in a clinical setting in index patients with clinical signs of DCM/ACM, or in family members of p.Arg14del carriers. We collected clinical data from the first cardiac evaluation and follow-ups. Malignant VAs were defined as sustained VA, appropriate ICD intervention or (aborted) sudden cardiac death. A prediction model was developed using Cox Proportional Hazard regression. Candidate baseline predictors were pre specified based on literature and clinical expertise. Age, sex, proband status, sudden cardiac death (SCD) in 1st degree relative, repolarization abnormalities, microvoltages, premature ventricular complexes (PVC) burden on 24hrs Holter monitoring, LVEF and non-sustained ventricular arrhythmias (NSVT) were considered. The multivariable model was fitted using stepwise backward selection based on Akaike's Information Criterion. Results We included 440 p.Arg14del carriers with a mean age of 41±18 years and 41% males. During a median follow-up of 4.7 years (IQR 1.7–7.3), 44 incident malignant VA occurred, 20 sustained VAs and 24 appropriate ICD therapies. The multivariable HR's of selected predictors were: 2.2 for minor and 4.5 for major repolarization abnormalities vs no abnormalities (p value respectively 0.06 and 0.01), 2.2 for LVEF 500PVC/24hrs (p value 0.003). Carriers with and without events could be accurately distinguished with this model, with an optimism corrected C-statistic of 0.81. The model calibrated well, with agreement of observed and predicted 5 year malignant VA risk. Risk groups were split into quintiles of predicted risk, figure 1 shows the Kaplan Meier curve of incident malignant VA per risk group. The 5 year risk of incident malignant VA in the lowest 3 quintiles was 0%, 9% in the 4th quintile and 25.2% in the highest quintile. Conclusion We created a PLN p.Arg14del mutation specific prediction model to estimate risk of incident malignant VA. With this model a clear distinction between high risk and low risk patients can be made and can be used to guide ICD implantation for primary prevention.

Background: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. Objective: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL.Methods: A NGS gene panel was analysed in 24 patients with EL.Results: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected.Conclusion: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition. (C) 2017 Elsevier Masson SAS. All rights reserved.

Rationale: Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated. Objective: We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause. Methods and Results: As in dopamine β-hydroxylase deficiency, concentrations of norepinephrine and epinephrine in the patients were low. Plasma dopamine β-hydroxylase activity, however, was normal, and the DBH gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause. Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 ( CYB561 ); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family. Expression of CYB561 was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA, and real-time quantitative polymerase chain reaction. The CYB561 gene was found to be expressed in many human tissues, in particular the brain. The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional dopamine β-hydroxylase deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of 6 CYB561 knockout mice (reporter-tagged deletion allele [post-Cre], genetic background C57BL/6NTac). The concentration of norepinephrine and normetanephrine was decreased in whole-brain homogenates of the CYB561 (− /− ) mice compared with wild-type mice ( P P l -dihydroxyphenylserine, which can be converted directly to norepinephrine. Conclusions: This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in CYB561 cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.

Arrhythmogenic cardiomyopathy (AC), also known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), is a hereditary disease characterised by ventricular arrhythmias, right ventricular and/or left ventricular dysfunction, and fibrofatty replacement of cardiomyocytes. Patients with AC typically present between the second and the fourth decade of life with ventricular tachycardias. However, sudden cardiac death (SCD) may be the first manifestation, often at young age in the concealed stage of disease. AC is diagnosed by a set of clinically applicable criteria defined by an international Task Force. The current Task Force Criteria are the essential standard for a correct diagnosis in individuals suspected of AC. The genetic substrate for AC is predominantly identified in genes encoding desmosomal proteins. In a minority of patients a non-desmosomal mutation predisposes to the phenotype. Risk stratification in AC is imperfect at present. Genotype-phenotype correlation analysis may provide more insight into risk profiles of index patients and family members. In addition to symptomatic treatment, prevention of SCD is the most important therapeutic goal in AC. Therapeutic options in symptomatic patients include antiarrhythmic drugs, catheter ablation, and ICD implantation. Furthermore, patients with AC and also all pathogenic mutation carriers should be advised against practising competitive and endurance sports.

Roberts JD, Herkert JC, Rutberg J, Nikkel SM, Wiesfeld ACP, Dooijes D, Gow RM, van Tintelen JP, Gollob MH. Detection of genomic deletions of PKP2 in arrhythmogenic right ventricular cardiomyopathy. Clin Genet 2013: 83: 452-456. (C) John Wiley & Sons A/S. Published by Blackwell Publishing Ltd, 2012 Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease that predominantly affects the right ventricle and is associated with ventricular arrhythmias that may lead to sudden cardiac death. Mutations within at least seven separate genes have been identified to cause ARVC, however a genetic culprit remains elusive in approximately 50% of cases. Although negative genetic testing may be secondary to pathogenic mutations within undiscovered genes, an alternative explanation may be the presence of large deletions or duplications involving known genes. These large copy number variants may not be detected with standard clinical genetic testing which is presently limited to direct DNA sequencing. We describe two cases of ARVC possessing large deletions involving plakophilin-2 (PKP2) identified with microarray analysis and/or multiplex ligation-dependent probe amplification (MLPA) that would have been classified as genotype negative with standard clinical genetic testing. A deletion of the entire coding region of PKP2 excluding exon 1 was identified in patient 1 and his son. In patient 2, MLPA analysis of PKP2 revealed deletion of the entire gene with subsequent microarray analysis demonstrating a de novo 7.9Mb deletion of chromosome 12p12.1p11.1. These findings support screening for large copy number variants in clinically suspected ARVC cases without clear disease causing mutations following initial sequencing analysis.

Background Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We describe new families carrying the p.S13F or p.N342D DES mutations, the cardiac phenotype of all carriers, and the founder effects. Methods We collected the clinical details of all carriers of p.S13F or p.N342D. The founder effects were studied using genealogy and haplotype analysis. Results We identified three new index patients carrying the p.S13F mutation and two new families carrying the p.N342D mutation. In total, we summarised the clinical details of 39 p.S13F carriers (eight index patients) and of 21 p.N342D carriers (three index patients). The cardiac phenotype of p.S13F carriers is fully penetrant and severe, characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement. Although muscle weakness is a prominent and presenting symptom in p.N342D carriers, their cardiac phenotype is similar to that of p.S13F carriers. The founder effects of p.S13F and p.N342D were demonstrated by genealogy and haplotype analysis. Conclusion DRM may occur as an apparently isolated cardiological disorder. The cardiac phenotypes of the DES founder mutations p.S13F and p.N342D are characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement. Electronic supplementary material The online version of this article (doi:10.1007/s12471-011-0233-y) contains supplementary material, which is available to authorized users.

A 9-year-old boy with the classical type of EhlersDanlos syndrome (EDS) developed a symptomatic aneurysm of the superior mesenteric artery. His EDS diagnosis had been confirmed biochemically and genetically. Vascular complications are known to be associated with the vascular type of EDS, but this is the first report of a child with classical EDS who developed a major vascular complication. Clinicians should be aware that severe vascular complications albeit rare, can also occur in classical EDS. (c) 2012 Wiley Periodicals, Inc.

Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We provide (i) a literature review on DRM, including clinical manifestations, inheritance, molecular genetics, myopathology and management and (ii) a meta-analysis of reported DES mutation carriers, focusing on their clinical characteristics and potential genotype-phenotype correlations. Meta-analysis: DES mutation carriers (n = 159) with 40 different mutations were included. Neurological signs were present in 74% and cardiological signs in 74% of carriers (both neurological and cardiological signs in 49%, isolated neurological signs in 22%, and isolated cardiological signs in 22%). More than 70% of carriers exhibited myopathy or muscular weakness, with normal creatine kinase levels present in one third of them. Up to 50% of carriers had cardiomyopathy and around 60% had cardiac conduction disease or arrhythmias, with atrioventricular block as an important hallmark. Symptoms generally started during the 30s; a quarter of carriers died at a mean age of 49 years. Sudden cardiac death occurred in two patients with a pacemaker, suggesting a ventricular tachyarrhythmia as cause of death. The majority of DES mutations were missense mutations, mostly located in the 2B domain. Mutations in the 2B domain were predominant in patients with an isolated neurological phenotype, whereas head and tail domain mutations were predominant in patients with an isolated cardiological phenotype.

Pathogenic mutations in the phospholamban (PLN) gene may give rise to inherited cardiomyopathies due to its role in calcium homeostasis. Several PLN mutations have been identified, with the R14del mutation being the most prevalent cardiomyopathy-related mutation in the Netherlands. It is present in patients diagnosed with arrhythmogenic cardiomyopathy as well as dilated cardiomyopathy. Awareness of the phenotype of this PLN mutation is of great importance, since many carriers remain to be identified. Patients with the R14del mutation are characterised by older age at onset, low-voltage electrocardiograms and ahigh frequency of ventricular arrhythmias. Additionally, these patients have apoor prognosis often with left ventricular dysfunction and early-onset heart failure. Therefore, when there is asuspicion of aPLN mutation, cardiac and genetic screening is strongly recommended.

Background About 2-7% of familial cardiomyopathy cases are caused by a mutation in the gene encoding cardiac troponin 1 (TNNI3). The related clinical phenotype is usually severe with early onset. Here we report on all currently known mutations in the Dutch population and compared these with those described in literature.Methods TheTNNI3 gene was screened for mutations in all coding exons and flanking intronic sequences in a large cohort of cardiomyopathy patients. All Dutch index cases carrying a TNNI3 mutation that are described in this study underwent extensive cardiological evaluation and were listed by their postal codes.Results In 30 families, 14 different mutations were identified. Three TNNI3 mutations were found relatively frequently in both familial and non-familial cases of hypertrophic cardiomyopathy (HCM) or restrictive cardiomyopathy (RCM). Haplotype analysis showed that p. Arg145Trp and p.Ser166Phe are founder mutations in the Netherlands, while p.Glu209Ala is not. The majority of Dutch TNNI3 mutations were associated with a HCM phenotype. Mean age at diagnosis was 36.5 years. Mutations causing RCM occurred less frequently, but were identified in very young children with a poor prognosis.Conclusion In line with previously published data, we found TNNI3 mutations to be rare and associated with early onset and severe clinical presentation.

Background. Loeys-Dietz syndrome (LDS) is a newly recognised disorder of connective tissue which shares overlapping features with Marfan syndrome (MFS) and the vascular type of Ehlers-Danlos syndrome, including aortic root dilatation and skin abnormalities. It is clinically classified into types 1 and 2. LDS type 1 can be recognised by craniofacial characteristics, e.g. hypertelorism, bifid uvula or cleft palate, whereas these are absent in LDS type 2. It is important to recognise LDS because its vascular pathology is aggressive. We describe nine LDS patients from four families, relate their features to published cases, and discuss important aspects of the diagnosis and management of LDS in order to make clinicians aware of this new syndrome. Results: Characteristics found in the majority of these LDS patients were aortic root dilatation, cleft palate and/or a bifid/abnormal uvula. Conclusion: Because aortic dissection and rupture in LDS tend to occur at a young age or at aortic root diameters not considered at risk in MFS, and because the vascular pathology can be seen throughout the entire arterial tree, patients should be carefully followed up and aggressive surgical treatment is mandatory. Clinicians must therefore be aware of LDS as a cause of aggressive aortic pathology and that its distinguishing features can sometimes be easily recognised.

Contains fulltext : 48941.pdf (Publisher’s version ) (Closed access) Cerebral developmental abnormalities occur in various inborn errors of metabolism including peroxisomal deficiencies, pyruvate dehydrogenase complex deficiency and others. Associations with abnormalities of the respiratory chain are rare. Here we report male and female siblings with microcephaly, a complex neuromigrational disorder including ependymal cysts, leptomeningeal and subcortical heterotopia, polymicrogyria, multifocal cerebral calcifications, agenesis of the corpus callosum, and spongiform changes in brainstem and cerebellum. Intractable lactic acidosis, causing death on the first day of life, was associated with severely reduced activities of complex I and complex IV. The neuropathological and biochemical findings are closely similar to those reported previously. The findings confirm a distinct genetic syndrome of disrupted brain development with TORCH-like calcifications, and a complex neuronal migration disorder associated with a multicomplex disorder of the respiratory chain.

Objectives: To assess the psychological effect of predictive testing in parents of children at risk for long QT syndrome (LQTS) in a prospective study.Methods: After their child was clinically screened by electrocardiography and blood was taken for DNA analysis, and shortly after delivery of the DNA test result, 36 parents completed measures of psychological distress. Results: 24 parents were informed that at least one of their children is a mutation carrier. Up to 50% of the parents of carrier children showed clinically relevant high levels of distress. Parents who were familiar with the disease for a longer time, who had more experiences with the disease in their family and who received positive test results for all their children were most distressed. Conclusions: Predictive ECG testing together with DNA testing has a profound impact on parents whose minors undergo predictive testing for LQTS.

This exploratory study serves to illustrate the psychological impact on an extended family in the process of genetic counselling and testing for a potentially life-threatening arrhythmia, the long-QT syndrome (LQTS).All members of the third generation and their partners (n=11) were interviewed, the mutation carriers with partners twice. In addition they completed measures for anxiety and depression three times in 18 months.During the interviews these family members emphasised the damaged solidarity when the family is divided into carriers and noncarriers of a mutation in a LQTS predisposing gene. This demonstrates one way in which a family can react to the reality of being at risk of a potentially severe disease. Rewriting family history and mourning early death seem other ways to deal with this. The distress scores, especially of the women, were moderate to clinically high, not because of their own chance of having an arrhythmia but more due to their children's risk.Mothers need educational even more than emotional support, because the lifestyle of their carrier children is in need of radical change. The setting of a combined outpatient cardiogenetic clinic with a medical and psychosocial staff meets such needs efficiently.

We recently identified a novel mutation in large family characterised by premature nocturnal sudden death. In the present paper we provide an overview of the findings in this family.From 1958 onwards, when the first patient presented, we collected clinical data on as many family members as possible. After identification in 1998 of the underlying genetic disorder (SCN5A, 1795insD), genotyping was performed diagnostically.Since 1905 unexplained sudden death occurred in 26 family members, 17 of whom died during the night. Besides sudden death, symptomatology was rather limited; only six patients reported syncopal attacks. In one of them, a 13-year-old boy, asystolic episodes up to nine seconds were documented. Until now, the mutation has been found in 114 family members (57 males, 57 females). Carriers of the mutant gene exhibited bradycardia-dependent QT-prolongation, intrinsic sinus node dysfunction, generalised conduction abnormalities, a paucity of ventricular ectopy, and the Brugada sign. Cardiomyopathy or other structural abnormalities were not found in any of the carriers. Electrophysiological studies showed that mutant channels were characterised by markedly reduced IWe have described a large family with a SCN5A-linked disorder (1795insD) with features of LQT

INTRODUCTION: NGS techniques can be successfully applied to find mutations underlying genetic cardiomyopathies. However, Exome Sequencing (ES) shows incomplete representation and coverage of exons, leading to clinically relevant mutations being missed. Thus, ES will, at least for now, coexist in clinical genetic diagnostics with other NGS-based strategies, such as gene-panel based resequencing. Therefore, we aimed at evaluating the yield of gene-panel based resequencing of 55 genes in cardiomyopathy patients referred to our department. METHODS: We constructed an enrichment kit targeting 55 cardiomyopathy genes and implemented this into routine diagnostics. We evaluated our first 162 patients: 47 fulfilled generally accepted clinical criteria for hypertrophic cardiomyopathy (HCM), 72 fulfilled the Mestroni criteria for dilated cardiomyopathy (DCM) and 3 were diagnosed with arrhythmogenic cardiomyopathy (ACM). In addition, 23, 11 and 6 cases showed signs of DCM, HCM and ACM, yet did not fulfill the formal criteria. Additional cosegregation analyses were performed to further support pathogenicity of potentially causal mutations. RESULTS: In the DCM cohort 40 pathogenic or likely pathogenic mutations were identified (55%; 40/72). Mutations in TTN were found in 14% of DCM patients (10/72). The yield in criteria positive HCM and ACM patients was 40% (17/43) and 33% (1/3). In patients not fully fulfilling criteria for DCM, HCM and ACM the yield was 52% (12/23), 36% (4/11) and 83% (5/6). In 13 % (21/162) of cases two or more (potentially) pathogenic mutations were identified. Results of cosegregation analyses supported pathogenicity of potentially causal mutations in 42 families. In 6 results argued against pathogenicity. CONCLUSIONS: Gene-panel based NGS results in a substantial increase in diagnostic yield for DCM patients compared to previous results of Sanger sequencing most prevalent genes (55% vs 20-25%). TTN mutations are most prevalent in DCM patients (14%). Higher diagnostic yields are achieved for patients fulfilling DCM and HCM criteria. Cosegregation analyses further support pathogenicity of potentially causal mutations. Together, our gene-panel based approach greatly improved genetic diagnostics in cardiomyopathies.

Introduction: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is a hereditary progressive cardiomyopathy. We aimed to define long-term outcome in a transatlantic ARVD/C cohort of 1001 individuals. Methods: Clinical/genetic characteristics and follow-up data of ARVD/C index patients (n=439, fulfillment of 2010 criteria in all) and family members (n=562) were assessed. Genetic screening of desmosomal and TMEM43 and PLN genes was performed in index patients. Results: Mutations, predominantly in PKP2, were identified in 276/439 (63%). Index patients presented mostly with sustained ventricular arrhythmias (VA) (268/439, 61%). Recurrent sustained VA (in 301/416 (72%) patients presenting alive) characterized follow-up (median 7 years) with 10/63 (16%) sudden cardiac deaths (SCD) in patients without implantable cardioverter-defibrillators (ICDs) versus 2/335 (0.6%) in those with ICDs. Overall, cardiac mortality during follow-up (6%) and cardiac transplantation rate (4%) were low. Although disease onset was significantly earlier in index patients with mutations (first presentation 34 vs.38 years old, p Conclusions: Long-term outcome in ARVD/C index patients was favorable when diagnosed and treated. Prognosis in family members was determined by symptoms and mutation status. One in three family members, including asymptomatic mutation carriers, developed ARVD/C.

Background Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We describe new families carrying the p.S13F or p.N342D DES mutations, the cardiac phenotype of all carriers, and the founder effects. Methods We collected the clinical details of all carriers of p.S13F or p.N342D. The founder effects were studied using genealogy and haplotype analysis. Results We identified three new index patients carrying the p.S13F mutation and two new families carrying the p.N342D mutation. In total, we summarised the clinical details of 39 p.S13F carriers (eight index patients) and of 21 p.N342D carriers (three index patients). The cardiac phenotype of p.S13F carriers is fully penetrant and severe, characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement. Although muscle weakness is a prominent and presenting symptom in p.N342D carriers, their cardiac phenotype is similar to that of p.S13F carriers. The founder effects of p.S13F and p.N342D were demonstrated by genealogy and haplotype analysis. Conclusion DRM may occur as an apparently isolated cardiological disorder. The cardiac phenotypes of the DES founder mutations p.S13F and p.N342D are characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement.

Background. About 30% of dilated cardiomyopathy (DCM) cases are familial. Mutations are mostly found in the genes encoding lanain A/C, beta-myosin heavy chain and the sarcomeric protein cardiac troponin-T (TNNT2). Mutations in TNNT2 are reported in approximately 3% of DCM patients. The overall phenotype caused by TNNT2 mutations is thought to be a fully penetrant, severe disease. This also seems to be true for a recurrent deletion in the TNNT2 gene; p.K217del (also known as p.K210del). Methods. We compared the phenotype of all Dutch patients identified as carrying the TNNT2 p.K217de1 mutation with those described in the literature. All index patients underwent cardiological evaluation. Family screening was done in all described families. Results. Six DCM patients carrying the TNNT2 p.K217de1 mutation were identified from four Dutch families. Mean age of disease manifestation was 33 years. Heart transplantation was required in three of them at ages 12, 18 and 19 years. These outcomes are comparable with those described in the literature. Conclusion. Carriers of the TNNT2 p.K217de1 mutation in our Dutch families, as well as in families described in the literature before, generally show a severe, early-onset form of DCM. (Neth Heart J 2010;18:478-85.)

In this part of a series on founder mutations in the Netherlands, we review a Dutch family carrying the SCN5a 1795insD mutation. We describe the advances in our understanding of the premature sudden cardiac deaths that have accompanied this family in the past centuries. The mutation carriers show a unique overlap of long-QT syndrome (type 3), Brugada syndrome and progressive cardiac conduction defects attributed to a single mutation in the cardiac sodium channel gene SCN5a. It is at present one of the largest and best-described families worldwide and we have learned immensely from the mouse strains with the murine homologue of the SCN5a 1795insD mutation (SCN5a 1798insD). From the studies currently performed we are about to obtain new insights into the phenotypic variability in this monogenic arrhythmia syndrome, and this might also be relevant for other arrhythmia syndromes and the general population. (Neth Heart J 2009;17:422-8.19949711)

Introduction: Plakophilin-2 (PKP2) is the major genetic determinant of ARVD/C in the Netherlands. Mutations have been found in 43 out of 82 index cases (52%), diagnosed in accordance with the 1994 Task Force criteria (TFC). A total of 15 different mutations were detected, most of them nonsense (7), frameshift (2) and splice mutations (3), suggesting haploinsufficiency (loss of function) of PKP2 as the predominant mechanism in the etiology of ARVD/C. Since many of these mutations are probably functional null alleles, it was hypothesized that large deletions within - or encompassing - the PKP2 gene can also predispose to ARVD/C. Aim: to determine whether large deletions in PKP2 underlie apparently PKP2 negative ARVD/C cases. Methods: a multiple ligation-dependent probe amplification kit was developed to determine copy number of all 14 exons of the PKP2 gene. In total 120 patients were included that had been referred for PKP2 testing, and that had tested negative with direct sequencing or denaturing gradient gel electrophoresis. Twenty-six patients had definite ARVD/C (TFC: ≥ 4 pts), 11 patients scored 3 pts and 83 patients scored less than 3 pts or had insufficient clinical data. Results: a single deletion was detected encompassing the first 4 exons and promoter region of the PKP2 gene. The patient, a 35 year old male, had experienced near-syncope during exercise. Mild dilation of the right ventricle (1 pt), negative T-waves in V1-V5 (1 pt) and short VT’s with LBBB morphology during exercise testing were found (1 pt). There were frequent PVC’s. The father also carried the deletion. A third degree paternal relative died suddenly at age 28 during exercise. Conclusion: large genomic deletions of PKP2, that go unnoticed with sequencing, can cause ARVD/C-like disease. Comprehensive testing of PKP2 should include assessment of copy number. However, the frequency of large deletions seems to be low. Since the detected deletion includes the promoter and the transcription initiation site, no protein can be derived from the affected allele. This patient demonstrates that complete loss of one PKP2 allele does not necessarily lead to more severe ARVD/C. This is in keeping with the concept of haploinsufficiency and the assumption that many PKP2 mutations cause functional null alleles.

During the past decade, developments in the field of DNA diagnostics have resulted in the confirmation of the genetic nature of several cardiac diseases. In a cardiogenetics outpatient clinic, a cardiologist and a clinical geneticist together evaluate persons with a (possible) hereditary cardiac disease. It is of utmost importance that patients with hereditary cardiac diseases be recognised and subsequently referred for genetic counselling as several preventive and therapeutic options are available.

Can a parent adjust to the idea that its child is at risk for a sudden death? This question is raised by a diagnostic procedure in which children were tested for an inherited Long QT Syndrome (LQTS). This potentially life-threatening but treatable cardiac arrhythmia syndrome may cause sudden death, especially in children and young adults. The long-term psychological effects are described for parents whose children were tested for inherited LQTS. The adverse short-term impact of such testing has been described previously. The goal of this investigation is to determine whether this distress endures. Thirty-six parents completed measures of psychological distress. With the twenty-four parents of carrier children, a semi-structured interview was held 18 months after DNA disclosure. Parents of carrier children reported more distress than parents of non-carrier children. Parents of carrier children remained vulnerable to high levels of distress; up to one-third of these parents showed clinically relevant high levels of distress. High levels of distress were reported by parents of carrier children who (1) were highly distressed at previous assessments, (2) were familiar with the disease for a longer time, (3) had experienced a sudden death in the family, (4) were lesser educated, and who (5) were unsatisfied with the given information. Parents were particularly concerned about possible hazardous behavior during puberty. We conclude that the continuous threat of developing LQTS symptoms despite prophylactic treatment affected the psychological well-being of the parents for a long time. In light of the tempetuous developments in the areas of cardiac genetics, periodical information on new insight and developments may act as a buffer for the parents' (growing) concerns about their child's inherited disorder. (c) 2005 Wiley-Liss, Inc.

Two men aged 47 and 56 and one woman aged 21 presented at our cardiology department with presyncope, heart failure and exercise induced palpitations, respectively. Using the criteria of McKenna et al., a diagnosis of arrhythmogenic right-ventricular cardiomyopathy (ARVC) was made. Following implantation of a defibrillator, one of the men experienced seven appropriate interventions within six months and also developed psychological problems. The other man was problem-free and the woman recovered reasonably well, having only one appropriate intervention from the defibrillator one year after implantation. Indications of ARVC were also found in her mother but not in any other family members. Because ARVC manifests itself in various different ways it is difficult to diagnose. It is important to consider ARVC in patients with exercise-induced palpitations, presyncope, and unexplained cardiomyopathies or arrhythmias, especially if there is a family history of unexpected deaths. ARVC is a potentially life-threatening disease, that may require implantation of a cardioverter defibrillator. Furthermore, since genetics play an important role and ARVC can be asymptomatic, evaluation of close relatives for preclinical symptoms is important.

A 23-year-old female with familial long-QT syndrome and a 48-year-old male with familial dilated cardiomyopathy were given an implantable cardioverter-defibrillator (ICD) as prophylaxis. About half a year after the implantation, there was an appropriate and successful ICD-discharge in both patients in connection with ventricular tachycardia. Treatment with an ICD can be life-saving in patients with cardiac rhythm disorders. The most common indication is ventricular tachycardia or fibrillation due to ischaemic heart disease, but an ICD may also be indicated in patients with cardiomyopathy, congenital heart disease, hereditary arrhythmia or a planned heart transplantation.

Purpose: To examine the gross and microscopic pathological features of complete heart specimens from patients carrying the phospholamban (PLN) p.Arg14del mutation and to test our hypothesis that this mutation leads to aggregation and autophagy of mutant PLN protein in cardiomyocytes. Methods: Sixteen hearts were studied, acquired from 8 male and 8 female patients with a median age of 51.5 years (range 29-74). Eleven were obtained from autopsies and five were explants. Six autopsy cases had died suddenly. The other 10 patients were clinically evaluated on the basis of widely accepted criteria for ARVC and DCM. Immunohistochemistry (IHC) for PLN was performed to visualize protein aggregation. IHC for sequestosome-1 (SQSTM-1/p62) was applied to visualize autophagy. Double IHC staining was performed to study co-localization of PLN and SQSTM-1/p62 in aggregates. Results: All hearts had an ARVC phenotype with gross or microscopic fibrofatty replacement of the RV wall. LV involvement was present in 15/16 hearts, characterized by interstitial fibrosis and myocyte hypertrophy. Microscopic LV fibrofatty replacement was seen in 8/16 hearts. Clinically, 8/10 patients were diagnosed with combined ARVC/DCM and 2/10 had ARVC. Large perinuclear PLN protein aggregates were found in cardiomyocytes in both ventricles in all examined hearts. The median number of PLN aggregates was 8 per 5mm2 (range 1-19) in RV myocardium and 12 per 5mm2 (range 2-39) in LV myocardium. Co-localization of SQSTM-1/p62 and PLN was observed in these aggregates. Conclusions: In this series of 16 hearts, it appeared that PLN p.Arg14del-mutation related cardiomyopathy is a biventricular arrhythmogenic cardiomyopathy and a protein-aggregate associated disease characterized by large perinuclear PLN aggregates that are degraded by autophagy. ![Figure][1] Typical example gross pathological feat. [1]: pending:yes

Objectives, Background: Inflammation may contribute to disease progression in arrhythmogenic cardiomyopathy (AC) however, its role in this process is unresolved. Our goal was to delineate the pathogenic role of the complement system in a new animal model of AC and its involvement in human disease. Methods and Results: By cardiac histology, echocardiography, and electrocardiography we have demonstrated that the desmin-null mouse (Des-/-) recapitulates most of the pathognomonic features of human AC. Massive complement activation was observed in the Des-/- myocardium in areas of necrotic cells debris and inflammatory infiltrate. Analysis of C5aR-/-Des-/- double-null animals and a pharmaceutical approach using the C5a-neutralizing Spiegelmer were used to delineate the pathogenic role of the complement system in the disease progression. Our findings indicate that inhibiting C5aR (CD88) signaling appreciably improves cardiac function, histopathology, and arrhythmias. Containment of the inflammatory reaction at the initiation of cardiac tissue injury (at 2-3 weeks of age) with a consequently reduced myocardial remodelling and the absence of a direct long lasting detrimental effect of C5a-C5aR signaling on cardiomyocytes could explain the beneficial action of C5aR ablation in Des-/- cardiomyopathy. We substantiated the relevance of these findings to human pathophysiology by demonstrating, for the first time, significant complement activation in the cardiac tissues from patients with AC. Conclusions: Complement could be a valid target for treatment/amelioration of AC.

Precarious acrocentric short arm in prenatal diagnosis: no chromosome 14 polymorphism, but trisomy 17p: We report on a girl with multiple congenital abnormalities and a prenatally diagnosed 46,XX,14p+ de novo karyotype. Fluorescence in situ hybridization (FISH) demonstrated that the extra material on the short arm of chromosome 14 was not just a polymorphism, but that it originated from chromosome 17. The phenotypic findings of this patient with pure trisomy 17p are compared with those of ten previously published cases.

DNA diagnostics were carried out in a family after the long QT interval syndrome had been diagnosed in one of its members. The psychic reactions to this testing were different from those seen in other hereditary diseases such as Huntington's disease. This was probably due to the sudden and unexpected occurrence of the arrhythmia. The family members in whom clinical and DNA diagnostics gave purely negative findings were not relieved, owing to solidarity with the affected relatives. Their partners did not understand this response. The anxiety and concern of the gene carriers had nothing to do with their own health status but with that of their carrier children. These parents were in need of educational counselling and advice. The results of clinical and DNA diagnostics affected the family relationships: in carriers the feeling of closeness grew, while the non-carriers were afraid of loss of family closeness.

Sudden cardiac death without ischaemic heart disease may be due to a hereditary heart disease with an autosomal dominant heredity. The occurrence, if any, of sudden death in such a family is a main indicator for the risk of sudden cardiac death in other family members. Cardiological and/or genetic investigation may reveal a hereditary disease in relatives without symptoms. Of some of these pathological conditions, the corresponding chromosomal localizations and sometimes the gene mutations have been identified. The psychic burden of family investigation and the socio-economic consequences (insurances, occupation, family relationships) are potentially heavy. Prophylactic treatment of asymptomatic persons in whom a gene mutation is established may comprise advice about lifestyle (e.g. avoidance of peak exercise in patients with hypertrophic cardiomyopathy), medication (e.g. beta-receptor blockers in patients with a long QT interval) or implantation of a pacemaker or internal defibrillator (e.g. in asymptomatic persons with the Brugada syndrome, a form of right bundle branch block). Presymptomatic investigation must be performed multidisciplinary.

Congenital long QT syndrome (cLQTS) is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death. LQTS can occur either as an autosomal dominant (Romano Ward) or as an autosomal recessive disorder (Jervell and Lange-Nielsen syndrome). Mutations in at least five genes have been associated with the LQTS. Four genes, encoding cardiac ion channels, have been identified. The most common forms of LQTS are due to mutations in the potassium-channel genes KCNQ1 and HERG. We have screened 24 Dutch LQTS families for mutations in KCNQ1 and HERG. Fourteen missense mutations were identified. Eight of these missense mutations were novel: three in KCNQ1 and five in HERG. Novel missense mutations in KCNQ1 were Y184S, S373P, and W392R and novel missense mutations in HERG were A558P, R582C, G604S, T613M, and F640L. The KCNQ1 mutation G189R and the HERG mutation R582C were detected in two families. The pathogenicity of the mutations was based on segregation in families, absence in control individuals, the nature of the amino acid substitution, and localization in the protein. Genotype-phenotype studies indicated that auditory stimuli as trigger of cardiac events differentiate LQTS2 and LQTS1. In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. Asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analyses for unequivocal diagnosis of patients with LQTS.

Background Pathogenicity of truncating or splice site mutations in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients has been widely accepted. However, pathogenicity of missense variants remains controversial. We assessed pathogenicity of ARVC-related missense variants and associated phenotype. Methods Pathogenic mutations were found in 571 patients (239 families, age 43 ± 18 years) from US/Dutch ARVC cohorts by screening of desmosomal (PKP2, DSC2, DSG2, DSP, JUP) and/or nondesmosomal (PLN, TMEM43) genes. Patients with >1 mutation or variant were excluded. Missense variants were considered pathogenic when (1) algorithms SIFT and PolyPhen-2 predicted pathogenicity (SIFT: tolerance index score ≤0.05, PolyPhen-2: pathogenicity score >0.90) and (2) minor allele frequency in 1000 genomes was Results A pathogenic missense mutation was found in 86/571 patients (15%). Frequently occurring mutation was PKP2 c.2386T>C (p.Cys796Arg; 34/86). Survival curves (P = .065) and, more importantly, sustained arrhythmia (ventricular tachycardia/fibrillation or appropriate ICD therapy) free survival curves (P = .810) of patients with a missense mutation were similar to those with pathogenic non-missense (330/571 truncating, 129/571 splice site) mutations (Figure). Conclusions ARVC-related missense mutations have a similar pathogenic character as non-missense mutations regarding survival and substantial arrhythmic burden. Pathogenicity of missense mutations can be correctly predicted by combined criteria from SIFT, PolyPhen-2, and 1000 genomes. Download : Download high-res image (120KB) Download : Download full-size image

Congenital long RT syndrome (cLQTS) is electrocardiographically characterized by a prolonged RT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death. LQTS can occur either as an autosomal dominant (Romano Ward) or as an autosomal recessive disorder (Jervell and Lange-Nielsen syndrome). Mutations in at least five genes have been associated with the LQTS. Four genes, encoding cardiac ion channels, have been identified. The mast common forms of LQTS are due to mutations in the potassium-channel genes KCNQ1 and HERG, We have screened 24 Dutch LQTS families for mutations in KCNQ1 and HERG, Fourteen missense mutations were identified. Eight of these missense mutations were novel: three in KCNQ1 and five in HERG, Novel missense mutations in KCNQ1 were Y184S, S373P, and W392R and novel missense mutations in HERG were A558P, R582C, G604S, T613M, and F640L. The KCNQ1 mutation G189R and the HERG mutation R582C were detected in two families. The pathogenicity of the mutations was based on segregation in families, absence in control individuals, the nature of the amino acid substitution, and localization in the protein. Genotype-phenotype studies indicated that auditory stimuli as trigger of cardiac events differentiate LQTS2 and LQTS1, In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. Asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analyses for unequivocal diagnosis of patients with LQTS. Hum Mutat 13:301-310, 1999, (C) 1999 Wiley-Liss, Inc.