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Background: Familial idiopathic ventricular fibrillation (IVF) is a severe disease entity and is notoriously difficult to manage because there are no clinical risk indicators for premature cardiac arrest. Previously, we identified a link between familial IVF and a risk haplotype on chromosome 7q36 (involving the arrhythmia gene DPP6)., Objective: The purpose of this study was to expand our knowledge of familial IVF and to discuss its (extended) clinical characteristics., Methods: We studied 601 family members and probands: 286 DPP6 risk-haplotype positive (haplotype-positive) and 315 DPP6 risk-haplotype negative (haplotype-negative) individuals. Clinical parameters, a combination of all-cause mortality and (aborted) cardiac arrest and differences between haplotype-positives and haplotype-negatives, were evaluated., Results: There were no differences in electrocardiographic indices between haplotype-positives and haplotype-negatives, or between haplotype-positives with or without events. Cardiac magnetic resonance documented slightly larger ventricular volumes in haplotype-positives compared to controls (P <.05), but these were not clinically useful. Mortality and/or cardiac arrest occurred in 85 haplotype-positives (30%) and 18 haplotype-negatives (6%). Twenty-four haplotype-positives (8% male) were resuscitated from ventricular fibrillation (VF). Documented VF was always elicited by monomorphic short-coupled extrasystoles from the right ventricular apex/lower free wall. Median survival in risk-haplotype haplotype-positives was 70 vs. 93 years for haplotype-negatives (P < .01), with a worse phenotype in males (median survival 63 vs. 83 years in females, P < .01). Implantable cardioverter-defibrillators were implanted in 99 patients (76 [77%] for primary prevention). Two arrhythmic events occurred in the primary prevention group during follow-up (5 ± 3 years)., Conclusion: Despite our extensive analysis, the complexity in identifying asymptomatic IVF family members at risk for future arrhythmias based on clinical parameters is once more demonstrated., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Knowledge on children's capacities to consent to medical treatment is limited. Also, age limits for asking children's consent vary considerably between countries. Decision-making on predictive genetic testing (PGT) is especially complicated, considering the ongoing ethical debate. In order to examine just age limits for alleged competence to consent in children, we evaluated feasibility of a standardized assessment tool, and investigated cutoff ages for children's competence to consent to PGT. We performed a pilot study, including 17 pediatric outpatients between 6 and 18 years at risk for an autosomal dominantly inherited cardiac disease, eligible for predictive genetic testing. The reference standard for competence was established by experts trained in the relevant criteria for competent decision-making. The MacArthur Competence Assessment Tool for Treatment (MacCAT-T) served as index test. Data analysis included raw agreement between competence classifications, difference in mean ages between children judged competent and judged incompetent, and estimation of cutoff ages for judgments of competence. Twelve (71 %) children were considered competent by the reference standard, and 16 (94 %) by the MacCAT-T, with an overall agreement of 76 %. The expert judgments disagreed in most cases, while the MacCAT-T judgments agreed in 65 %. Mean age of children judged incompetent was 9.3 years and of children judged competent 12.1 years (p = .035). With 90 % sensitivity, children younger than 10.0 years were judged incompetent, with 90 % specificity children older than 11.8 years were judged competent. Feasibility of the MacCAT-T in children is confirmed. Initial findings on age cutoffs are indicative for children between the age of 12 and 18 to be judged competent for involvement in the informed consent process. Future research on appropriate age-limits for children's alleged competence to consent is needed.

Background: Prophylactic implantable cardioverter defibrillator (ICD) therapy prevents sudden cardiac death (SCD) among young adults with cardiogenetic conditions, but might reduce quality of life (QoL) due to potential device complications, ongoing medical appointments, and lifestyle restrictions. We investigated QoL in the first year after ICD implantation for the primary prevention of SCD and compared QoL scores with population norms., Methods: Consecutive patients with cardiogenetic conditions (aged 18-50 years) referred to the Academic Medical Center in Amsterdam to receive ICD therapy for the primary prevention of SCD between 2007 and 2009 were eligible. Patients completed questions about QoL (Short-Form 36 Health Survey; SF-36), depressive symptoms (Center for Epidemiologic Studies Depression scale; CES-D), anxiety (State-Trait Anxiety Inventory; STAI), and the impact of receiving ICD therapy on lifestyle and work, shortly before ICD implantation and after 2 months, 6 months, and 12 months., Results: Thirty-five of 47 eligible patients participated. QoL was significantly reduced shortly before and 2 months after ICD implantation but improved over time and was comparable with population norms at 6 months and 12 months after ICD implantation. Yet, only about half of the patients believed they had a normal life like everyone else, and 28% had lost or changed their job due to their cardiogenetic condition and ICD therapy., Conclusions: Receiving a diagnosis of a cardiogenetic condition and subsequent ICD implantation was accompanied with a temporarily reduced QoL and a significant negative impact on professional life. Clinicians should inform their patients of the possible QoL consequences when deciding about ICD implantation in primary prevention of SCD in cardiogenetic conditions., (© 2015 Wiley Periodicals, Inc.)

Aim: Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort., Methods and Results: In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes., Conclusion: This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: Familial forms of primary sinus bradycardia have sometimes been attributed to mutations in HCN4, SCN5A, and ANK2. In these studies, no structural cardiac alterations were reported in mutation carriers. However, a cluster of reports in the literature describe patients presenting with sinus bradycardia in association with left ventricular noncompaction cardiomyopathy (LVNC), pointing to a shared genetic cause., Objectives: This study sought to identify the genetic defect underlying the combined clinical presentation of bradycardia and LVNC, hypothesizing that these 2 clinical abnormalities have a common genetic cause., Methods: Exome sequencing was carried out in 2 cousins from the index family that were affected by the combined bradycardia-LVNC phenotype; shared variants thus identified were subsequently overlaid with the chromosomal regions shared among 5 affected family members that were identified using single nucleotide polymorphism array analysis., Results: The combined linkage analysis and exome sequencing in the index family identified 11 novel variants shared among the 2 affected cousins. One of these, p.Gly482Arg in HCN4, segregated with the combined bradycardia and LVNC phenotype in the entire family. Subsequent screening of HCN4 in 3 additional families with the same clinical combination of bradycardia and LVNC identified HCN4 mutations in each. In electrophysiological studies, all found HCN4 mutations showed a more negative voltage dependence of activation, consistent with the observed bradycardia., Conclusions: Although mutations in HCN4 have been previously linked to bradycardia, our study provides the first evidence to our knowledge that mutations in this ion channel gene also may be associated with structural abnormalities of the myocardium., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The pathogenic phospholamban R14del mutation causes dilated and arrhythmogenic right ventricular cardiomyopathies and is associated with an increased risk of malignant ventricular arrhythmias and end-stage heart failure. We performed a multicentre study to evaluate mortality, cardiac disease outcome, and risk factors for malignant ventricular arrhythmias in a cohort of phospholamban R14del mutation carriers., Methods and Results: Using the family tree mortality ratio method in a cohort of 403 phospholamban R14del mutation carriers, we found a standardized mortality ratio of 1.7 (95% confidence interval, 1.4-2.0) with significant excess mortality starting from the age of 25 years. Cardiological data were available for 295 carriers. In a median follow-up period of 42 months, 55 (19%) individuals had a first episode of malignant ventricular arrhythmias and 33 (11%) had an end-stage heart failure event. The youngest age at which a malignant ventricular arrhythmia occurred was 20 years, whereas for an end-stage heart failure event this was 31 years. Independent risk factors for malignant ventricular arrhythmias were left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia with hazard ratios of 4.0 (95% confidence interval, 1.9-8.1) and 2.6 (95% confidence interval, 1.5-4.5), respectively., Conclusions: Phospholamban R14del mutation carriers are at high risk for malignant ventricular arrhythmias and end-stage heart failure, with left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia as independent risk factors. High mortality and a poor prognosis are present from late adolescence. Genetic and cardiac screening is, therefore, advised from adolescence onwards., (© 2014 American Heart Association, Inc.)

Aims: Disease mechanisms regarding hypertrophic cardiomyopathy (HCM) are largely unknown and disease onset varies. Sarcomere mutations might induce energy depletion for which until now there is no direct evidence at sarcomere level in human HCM. This study investigated if mutations in genes encoding myosin-binding protein C (MYBPC3) and myosin heavy chain (MYH7) underlie changes in the energetic cost of contraction in the development of human HCM disease., Methods and Results: Energetic cost of contraction was studied in vitro by measurements of force development and ATPase activity in cardiac muscle strips from 26 manifest HCM patients (11 MYBPC3mut, 9 MYH7mut, and 6 sarcomere mutation-negative, HCMsmn). In addition, in vivo, the ratio between external work (EW) and myocardial oxygen consumption (MVO2) to obtain myocardial external efficiency (MEE) was determined in 28 pre-hypertrophic mutation carriers (14 MYBPC3mut and 14 MYH7mut) and 14 healthy controls using [(11)C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging. Tension cost (TC), i.e. ATPase activity during force development, was higher in MYBPC3mut and MYH7mut compared with HCMsmn at saturating [Ca(2+)]. TC was also significantly higher in MYH7mut at submaximal, more physiological [Ca(2+)]. EW was significantly lower in both mutation carrier groups, while MVO2 did not differ. MEE was significantly lower in both mutation carrier groups compared with controls, showing the lowest efficiency in MYH7 mutation carriers., Conclusion: We provide direct evidence that sarcomere mutations perturb the energetic cost of cardiac contraction. Gene-specific severity of cardiac abnormalities may underlie differences in disease onset and suggests that early initiation of metabolic treatment may be beneficial, in particular, in MYH7 mutation carriers., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: Lamin A/C (LMNA) mutation carriers suffer from a variety of clinical phenotypes, including dilated cardiomyopathy (DCM). Although it has been suggested that carriers are at risk for thromboembolic complications, it is unknown whether this risk is higher than can be expected from the underlying cardiac abnormalities. The purpose of this study was to determine whether a LMNA mutation is associated with an increased risk of thromboembolic complications., Methods: We compared a cohort of 76 LMNA mutation carriers with a cohort of 224 idiopathic DCM patients without a LMNA mutation, with respect to the prevalence of arterial and venous thromboembolic complications. Furthermore, we carried out a case-control study to explore whether a prothrombotic phenotype was present in LMNA mutation carriers without DCM or atrial tachyarrhythmias (n=14) and compared this with mutation negative relatives (n=13)., Results: The prevalence of thromboembolic complications was higher in the cohort of LMNA mutation carriers than in DCM patients (22 vs 11%; p<0.05), after respectively mean follow-up of 42 ± 12 and 49 ± 12 years. After adjustment for possible confounders, including atrial tachyarrhythmias and left ventricular ejection fraction, LMNA mutation carriership was independently associated with an increased risk of thromboembolic complications (HR 4.8, 95% CI: 2.2-10.6). The results of the case-control study suggested a prothrombotic phenotype in LMNA mutation carriers, as reflected by an altered platelet function and increased thrombin generation., Conclusions: LMNA mutation is independently associated with an increased risk of arterial and venous thromboembolic complications. Laboratory research in LMNA mutation carriers without severe cardiac abnormalities suggests a prothrombotic phenotype., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Genetic evaluation of cardiomyopathies poses a challenge. Multiple genes are involved but no clear genotype-phenotype correlations have been found so far. In the past, genetic evaluation for hypertrophic (HCM) and dilated (DCM) cardiomyopathies was performed by sequential screening of a very limited number of genes. Recent developments in sequencing have increased the throughput, enabling simultaneous screening of multiple genes for multiple patients in a single sequencing run., Objective: Development and implementation of a next generation sequencing (NGS) based genetic test as replacement for Sanger sequencing., Methods and Results: In order to increase the number of genes that can be screened in a shorter time period, we enriched all exons of 23 of the most relevant HCM and DCM related genes using on-array multiplexed sequence capture followed by massively parallel pyrosequencing on the GS-FLX Titanium. After optimisation of array based sequence capture it was feasible to reliably detect a large panel of known and unknown variants in HCM and DCM patients, whereby the unknown variants could be confirmed by Sanger sequencing., Conclusions: The rate of detection of (pathogenic) variants in both HCM and DCM patients was increased due to a larger number of genes studied. Array based target enrichment followed by NGS showed the same accuracy as Sanger sequencing. Therefore, NGS is ready for implementation in a diagnostic setting.

Left ventricular noncompaction (LVNC) is a relatively common genetic cardiomyopathy, characterized by prominent trabeculations with deep intertrabecular recesses in mainly the left ventricle. Although LVNC often occurs in an isolated entity, it may also be present in various types of congenital heart disease (CHD). The most prevalent CHD in LVNC is Ebstein anomaly, which is a rare form of CHD characterized by apical displacement and partial fusion of the septal and posterior leaflet of the tricuspid valve with the ventricular septum. Several reports of sporadic as well as familial cases of Ebstein anomaly associated with LVNC have been reported. Recent studies identified mutations in the MYH7 gene, encoding the sarcomeric β-myosin heavy chain protein, in patients harboring this specific phenotype. Here, we will review the association between Ebstein anomaly, LVNC and mutations in MYH7, which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance., (Copyright © 2013 Wiley Periodicals, Inc.)

Aims: With more than 40 dilated cardiomyopathy (DCM)-related genes known, genetic analysis of patients with idiopathic DCM is costly and time-consuming. We describe the yield from genetic analysis in DCM patients in a large Dutch cohort., Methods and Results: We collected cardiological and neurological evaluations, family screenings, and genetic analyses for 418 index patients with idiopathic DCM. We identified 35 (putative) pathogenic mutations in 82 index patients (20%). The type of DCM influenced the yield, with mutations found in 25% of familial DCM cases, compared with 8% of sporadic DCM cases and 62% of cases where DCM was accompanied by neuromuscular disease. A PLN founder mutation (43 cases) and LMNA mutations (19 cases, 16 different mutations) were most prevalent and often demonstrated a specific phenotype. Other mutations were found in: MYH7, DES, TNNT2, DMD, TPM1, DMPK, SCN5A, SGCB (homozygous), and TNNI3. After a median follow-up of 40 months, the combined outcome of death from any cause, heart transplantation, or malignant ventricular arrhythmias in patients with a mutation was worse than in those without an identified mutation (hazard ratio 2.0, 95% confidence interval 1.4-3.0). This seems to be mainly attributable to a high prevalence of malignant ventricular arrhythmias and end-stage heart failure in LMNA and PLN mutation carriers., Conclusion: The yield of identified mutations in DCM index patients with clinical clues, such as associated neuromuscular disease or familial occurrence, is higher compared with those without these clues. For sporadic DCM, specific clinical characteristics may be used to select cases for DNA analysis.

Aims: Mutations in the lamin A/C gene (LMNA) cause a variety of clinical phenotypes, including dilated cardiomyopathy. LMNA is one of the most prevalent mutated genes in dilated cardiomyopathy, and is associated with a high risk of arrhythmias, sudden cardiac death, and heart failure. There are few data on the impact of age and gender on cardiac disease penetrance and mortality., Methods and Results: In a multicentre cohort of 269 LMNA mutation carriers, we evaluated gender-specific penetrance of cardiac involvement and major cardiac events. All-cause mortality of mutation carriers [standardized mortality ratio (SMR)] was determined. Cardiac disease penetrance was age dependent and almost complete at the age of 70 years. The presence of an LVEF ≤45% was significantly higher in men (P < 0.001). However, there was no difference between genders in the prevalence of atrioventricular block, atrial tachyarrhythmias, and non-sustained ventricular tachycardia. Malignant ventricular arrhythmias (26% vs. 8%) and end-stage heart failure (28% vs. 14%) were more common in men than in women (P < 0.001 and P = 0.006, respectively). All-cause mortality of mutation carriers was significantly increased [SMR 4.0, 95% confidence interval (CI) 2.8-5.2] between the ages of 15 and 75 years. Mortality in men was higher than in women (hazard ratio 2.2, 95% CI 1.2-4.3)., Conclusions: This large cohort of LMNA mutation carriers demonstrates a high cardiac disease penetrance and a high mortality in mutation carriers. Male mutation carriers have a worse prognosis due to a higher prevalence of malignant ventricular arrhythmias and end-stage heart failure.

Background: Dilated cardiomyopathy (DCM) is characterized by idiopathic dilatation and systolic contractile dysfunction of the ventricle(s) leading to an impaired systolic function. The origin of DCM is heterogeneous, but genetic transmission of the disease accounts for up to 50% of the cases. Mutations in alpha-tropomyosin (TPM1), a thin filament protein involved in structural and regulatory roles in muscle cells, are associated with hypertrophic cardiomyopathy (HCM) and very rarely with DCM., Methods and Results: Here we present a large four-generation family in which DCM is inherited as an autosomal dominant trait. Six family members have a cardiomyopathy with the age of diagnosis ranging from 5 months to 52 years. The youngest affected was diagnosed with dilated and non-compaction cardiomyopathy (NCCM) and died at the age of five. Three additional children died young of suspected heart problems. We mapped the phenotype to chromosome 15 and subsequently identified a missense mutation in TPM1, resulting in a p.D84N amino acid substitution. In addition we sequenced 23 HCM/DCM genes using next generation sequencing. The TPM1 p.D84N was the only mutation identified. The mutation co-segregates with all clinically affected family members and significantly weakens the binding of tropomyosin to actin by 25%., Conclusions: We show that a mutation in TPM1 is associated with DCM and a lethal, early onset form of NCCM, probably as a result of diminished actin binding caused by weakened charge-charge interactions. Consequently, the screening of TPM1 in patients and families with DCM and/or (severe, early onset forms of) NCCM is warranted. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Aims: To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM)., Methods and Results: We screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 %) ARVC patients and in 39 (15 %) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 % of R14del carriers. Compared with R14del- DCM patients, R14del+ DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 % vs. 10 % , P < 0.001), cardiac transplantation (18 % vs. 2 % , P < 0.001), and a family history for sudden cardiac death (SCD) at < 50 years (36 % vs. 16 % , P = 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 %) R14del+ ARVC samples, but in only one of nine (11 %) R14del+ DCM samples (P = 0.03)., Conclusions: The PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del+ patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of 'arrhythmogenic cardiomyopathy'.

The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P=0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM.

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease. A recent study showed that male KLF10-encoded TGFβ Inducible Early Gene-1 knock-out mice (TIEG-/-) develop HCM with 13-fold up-regulation of PTTG1-encoded pituitary tumor-transforming gene 1. We hypothesized TIEG1 could be a novel candidate gene in the pathogenesis of genotype negative HCM in humans, possibly through a loss of its repression on PTTG1 expression. A cohort of 923 unrelated patients from two independent HCM centers was analyzed for mutations in TIEG's four translated exons using DHPLC and direct DNA-sequencing. Site directed mutagenesis was performed to clone novel variants. The effect of TIEG1 mutations on SMAD7 and PTTG1 promoters was studied using transient transfection and luciferase-assays. Altered expression of PTTG1 in cardiac tissue was studied by immunohistochemistry (IHC) to determine levels of PTTG1 protein in hypertrophic diseases. Six novel TIEG1 missense mutations were discovered in six patients (two males/four females, mean age at diagnosis 56.2±23 years, MLVWT 20.8±4 mm). Compared to WT TIEG1, five TIEG1 mutants significantly increased PTTG1 promoter function similar to TIEG1-/--mice. By IHC, PTTG1-protein expression was significantly increased in multiple models of hypertrophic cardiac disease, including TIEG1-mutation positive HCM compared to normal hearts. This is the first article to associate mutations in TIEG1 to human disease with the discovery of six novel, HCM-associated variants. Functional assays suggest a role for PTTG1 in the pathogenesis of TIEG1-mediated HCM. Up-regulation of PTTG1 seems to be a common pathway in hypertrophic heart disease, including TIEG1-mediated HCM., (Copyright © 2012 Wiley Periodicals, Inc.)

Aims: Crypts can be found with cardiovascular magnetic resonance imaging (CMR) in hypertrophic cardiomyopathy (HCM) mutation carriers without hypertrophy (carriers) using a modified two-chamber view through the inferoseptum, but also in other patients and healthy individuals with standard long-axis views. Since it is currently unknown if carriers display a specific crypt morphology, we compared crypts in carriers with other cardiac pathologies (controls). Besides, we aimed to determine the optimal imaging plane for the detection of crypts by comparing modified two-chamber views with standard long-axis views. Finally, we evaluated the accuracy of crypts to identify carriers in HCM family screening., Methods and Results: Standard CMR long-axis views with additional modified two-chamber views were prospectively performed in carriers (n= 43), consecutive CMR control patients (n= 252), and mutation-negative family members (n= 15). Crypts were found in 70% (30/43) of carriers and in 12% (31/252) of controls (P< 0.001). Crypts in carriers showed deeper penetrance into the myocardium compared with controls (74 ± 21% vs. 59 ± 22%, P< 0.01). Detection of two or more crypts had a sensitivity of 51% and specificity of 94% for carriership. Modified two-chamber views doubled the sensitivity to detect crypts compared with standard long-axis views. In family screening, ≥2 crypts had a 100% positive predictive value to identify carriers., Conclusions: Multiple crypts in the absence of left ventricular hypertrophy are highly specific for HCM mutation carriership and warrant clinical follow-up. A modified two-chamber view has a superior sensitivity compared with standard long-axis views for crypt detection. CMR may be of additional value to identify carriers in family screening.

Schwannomatosis is a rare hereditary cancer syndrome in which patients develop multiple non-vestibular schwannomas. The chromatin remodelling gene SMARCB1 (also known as INI1, hSNF5, and BAF47) has been identified as a schwannomatosis predisposing gene, being involved in a subset of sporadic and familial cases. Recent studies have shown that SMARCB1 may also be involved in the development of multiple meningiomas. Previously, we demonstrated that the SMARCB1 exon 2 missense mutation c.143 C > T segregates with the presence of meningiomas in five members of a large family with multiple meningiomas and schwannomas. We extended our genetic analyses by screening 44 additional at-risk family members and identified 13 new carriers. Eleven of these were subjected to magnetic resonance imaging (MRI) of brain and spine. In addition, we analyzed four meningiomas and two schwannomas from family members for the presence of schwannomatosis-specific changes. We found in each tumor retention of the SMARCB1 exon 2 mutation, acquisition of an independent neurofibromatosis type 2 (NF2) gene mutation, and loss of heterozygosity at SMARCB1 and NF2 by loss of the wild-type copy of both genes. The MRI scans revealed one or more falx meningiomas in seven of 11 (64%) newly identified SMARCB1 mutation carriers. We conclude that the SMARCB1 exon 2 missense mutation in this family predisposes to the development of meningiomas as well as schwannomas, occurring via the same genetic pathways, and that this mutation preferentially induces cranial meningiomas located at the falx cerebri.

Aims: Next to left ventricular (LV) hypertrophy, hypertrophic cardiomyopathy (HCM) is characterized by microvascular dysfunction and reduced myocardial external efficiency (MEE). Insights into the presence of these abnormalities as early markers of disease are of clinical importance in risk stratification, and development of therapeutic approaches. Therefore, the aim was to investigate myocardial perfusion and energetics in genotype-positive, phenotype-negative HCM subjects (carriers)., Methods and Results: Fifteen carriers of an MYBPC3 mutation underwent [(15)O]water positron emission tomography (PET) to assess myocardial blood flow (MBF). [(11)C]acetate PET was performed to obtain myocardial oxygen consumption (MVO(2)). By use of cardiovascular magnetic resonance imaging, LV volumes and mass were defined to calculate MEE, i.e. the ratio between external work and MVO(2). Eleven healthy, genotype-negative, family relatives underwent similar scanning protocols to serve as a control group. Left ventricular mass was comparable between carriers and controls (93 ± 25 vs. 99 ± 21 g, P= 0.85), as was MBF at rest (1.19 ± 0.34 vs. 1.18 ± 0.32 mL min(-1) g(-1), P= 0.92), and during hyperaemia (3.87 ± 0.75 vs. 3.96 ± 0.86 mL min(-1) g(-1), P= 0.77). Myocardial oxygen consumption averaged 0.137 ± 0.057 mL min(-1) g(-1) in carriers and was not significantly different from controls (0.125 ± 0.043 mL min(-1) g(-1), P= 0.29). Cardiac work, however, was slightly reduced in carriers (7398 ± 1384 vs. 9139 ± 2484 mmHg mL in controls, P= 0.08). As a consequence, MEE was significantly decreased in carriers (27 ± 10 vs. 36 ± 8% in controls, P= 0.02)., Conclusion: Carriers display reduced myocardial work generation in relation to oxygen consumption, in the absence of hypertrophy and flow abnormalities. Hence, impaired myocardial energetics may constitute a primary component of HCM pathogenesis.

We describe 3 patients from a region in the centre of the Netherlands with several relatives who died prematurely from sudden cardiac arrest. These premature deaths appeared to be caused by a unique familial sudden death syndrome. These patients and their relatives did not present any distinguishable signs, symptoms or abnormalities on further examinations apart from premature cardiac arrest occurring in about 50% of the affected family members before the age of 60 years. Genetic analysis appeared to be the only means to identify family members at risk, carrying lethal changes in their DNA that presumably involve the DPP6-gene. Patients who survive a premature sudden cardiac arrest and relatives of patients who died prematurely from sudden cardiac arrest should be referred to a cardiogenetics outpatient clinic. Timely recognition of persons affected allows appropriate treatment and may implicate an implantable cardioverter defibrillator.

Aims: We investigated the presence of a clinical diagnosis of hypertrophic cardiomyopathy (HCM) and of risk factors for sudden cardiac death (SCD) at the first cardiological evaluation after predictive genetic testing in asymptomatic carriers of an MYBPC3 gene mutation., Methods and Results: Two hundred and thirty-five mutation carriers were cardiologically evaluated on the presence of HCM and risk factors. A clinical diagnosis of HCM was made in 53 carriers (22.6%). Disease penetrance at 65 years was incomplete for all types of MYBPC3 gene mutations. Women were affected less often than men (15 and 32% respectively, P = 0.003) and disease penetrance was lower in females than in males (13 and 30% at 50 years, respectively, P = 0.024). One risk factor was present in 87 carriers and 9 had two or more risk factors. Twenty-five carriers (11%) with one or more risk factors and manifest HCM could be at risk for SCD., Conclusion: At first cardiological evaluation almost one-quarter of asymptomatic carriers was diagnosed with HCM. Risk factors for SCD were frequently present and 11% of carriers could be at risk for SCD. Predictive genetic testing in HCM families and frequent cardiological evaluation on the presence of HCM and risk factors for SCD are justified until advanced age.

We performed a systematic literature review of recommended 'major' and 'possible' clinical risk markers for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). We searched the Medline, Embase and Cochrane databases for articles published between 1971 and 2007. We included English language reports on HCM patients containing follow-up data on the endpoint (sudden) cardiac death using survival analysis. Analysis was undertaken using the quality of reporting of meta-analyses (QUORUM) statement checklist. The quality was checked using a quality assessment form from the Cochrane Collaboration. Thirty studies met inclusion criteria and passed quality assessment. The use of the six major risk factors (previous cardiac arrest or sustained ventricular tachycardia, non-sustained ventricular tachycardia, extreme left ventricular hypertrophy, unexplained syncope, abnormal blood pressure response, and family history of sudden death) in risk stratification for SCD as recommended by international guidelines was supported by the literature. In addition, left ventricular outflow tract obstruction seems associated with a higher risk of SCD. Our systematic review provides sound evidence for the use of the six major risk factors for SCD in the risk stratification of HCM patients. Left ventricular outflow tract obstruction could be included in the overall risk profile of patients with a marked left ventricular outflow gradient under basal conditions.

Hypertrophic cardiomyopathy (HCM) is a common hereditary heart disease associated with increased mortality. Disclosure of DNA test results may have social implications such as low access to insurance. In The Netherlands, insurance companies are restricted in the use of genetic information of their clients by the Medical Examination Act. A cross-sectional survey was used to assess the frequency and type of problems encountered by HCM mutation carriers applying for insurance, and associations with carriers' characteristics. The response rate was 86% (228/264). A total of 66 carriers (29%) applied for insurance of whom 39 reported problems (59%) during an average follow-up of 3 years since the DNA test result. More problems were encountered by carriers with manifest disease (P<0.001) and carriers with symptoms of HCM (P=0.049). Carriers identified after predictive DNA testing less frequently experienced problems (P=0.002). Three carriers without manifest HCM reported problems (5% of applicants). Frequently reported problems were higher premium (72%), grant access to medical records (62%), and complete rejection (33%). In conclusion, HCM mutation carriers frequently encounter problems when applying for insurances, often in the case of manifest disease, but the risk assessment of insurance companies is largely justified. Still, 5% of carriers encounter potentially unjustified problems, indicating the necessity to monitor the application of the existing laws and regulations by insurance companies and to educate counselees on the implications of these laws and regulations.

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease with a clinical prevalence of 1 in 500. HCM is a monogenetic disease and is inherited autosomal dominantly. The disease can manifest itself at any age. Clinical presentation varies from symptom-free to severe dyspnoea and sudden cardiac death from ventricular arrhythmia. Diagnosis is mainly based on echocardiography and on MRI if necessary. In 50-60% of patients, molecular genetic investigation reveals a pathogenic mutation in one of the sarcomeric protein genes. The treatment of HCM depends on the symptoms and the potential presence of an obstruction in the left ventricular outflow tract. The risk of sudden cardiac death must be evaluated in order to determine if a prophylactic intracardiac defibrillator is necessary. In view of its mendelian form of inheritance, in the Netherlands practice guidelines have been issued recently regarding genetic counselling of the patient and his or her family and to initiate and coordinate research within the family.

Hypertrophic cardiomyopathy (HCM) is a common hereditary heart disease associated with sudden cardiac death. Predictive genetic counseling and testing are performed using adapted Huntington guidelines, that is, psychosocial care and time for reflection are not obligatory and the test result can be disclosed by telephone or mail. Proven mutation carriers detected by predictive DNA testing are advised to undergo regular cardiac follow-up according to international guidelines. We evaluated the opinion of 143 predictively tested HCM mutation carriers on received cardiogenetic care using questionnaires (response rate 86%). Predictive genetic counseling and DNA testing were evaluated on four domains: information provision, satisfaction with counseling, social pressure in DNA testing and regret of DNA testing. Opinions on cardiac follow-up were assessed pertaining to communication, nervous anticipation, reassurance, and general disadvantages. Genetic counseling was valued positively and only four carriers would rather not have known that they were a mutation carrier. A majority received their DNA test result by mail or telephone, and almost all were satisfied. Only 76% of carriers received regular cardiac follow-up. Those who did, had a positive attitude regarding the cardiac visits. General disadvantages of the visits were valued as low, especially by older carriers, men and carriers with manifest HCM. We conclude that our adapted Huntington guidelines are well accepted and that cardiogenetic care is generally appreciated by predictively tested HCM mutation carriers. To better understand the cause of the substantial portion of mutation carriers not receiving regular cardiac follow-up, although recommended in international guidelines, further research is needed.

Idiopathic Ventricular Fibrillation (IVF) is defined as spontaneous VF without any known structural or electrical heart disease. A family history is present in up to 20% of probands with the disorder, suggesting that at least a subset of IVF is hereditary. A genome-wide haplotype-sharing analysis was performed for identification of the responsible gene in three distantly related families in which multiple individuals died suddenly or were successfully resuscitated at young age. We identified a haplotype, on chromosome 7q36, that was conserved in these three families and was also shared by 7 of 42 independent IVF patients. The shared chromosomal segment harbors part of the DPP6 gene, which encodes a putative component of the transient outward current in the heart. We demonstrated a 20-fold increase in DPP6 mRNA levels in the myocardium of carriers as compared to controls. Clinical evaluation of 84 risk-haplotype carriers and 71 noncarriers revealed no ECG or structural parameters indicative of cardiac disease. Penetrance of IVF was high; 50% of risk-haplotype carriers experienced (aborted) sudden cardiac death before the age of 58 years. We propose DPP6 as a gene for IVF and increased DPP6 expression as the likely pathogenetic mechanism.

Hypertrophic cardiomyopathy (HCM) is a common hereditary heart disease associated with heart failure and sudden death. Quality of life and psychological distress were found to be impaired in HCM patients but have never been assessed in mutation carriers, with or without manifest HCM. We aimed to assess quality of life and psychological distress, using standardized questionnaires, and to identify sociodemographic, clinical, risk and illness perception related predictors thereof in 228 HCM mutation carriers. HCM carriers' overall quality of life and distress scores did not differ from the Dutch population. Quality of life and distress were worst in carriers with manifest HCM before DNA testing and best in predictively tested carriers without HCM. The latter group had even significantly better quality of life than the general population. Substantial determinants of impaired physical quality of life were symptoms (beta = 5.2, P = 0.001) and stronger belief in serious consequences of carriership (beta = 3.5, P < 0.001); determinants of impaired mental quality of life were physical comorbidity (beta = 3.0, P = 0.020) and a higher perceived risk of symptoms (beta = 0.9, P = 0.001). Female gender (beta = 1.4, P = 0.004) and stronger emotional reactions (beta = 1.2, P = 0.002) were associated with more anxiety. Less understanding of carriership (beta = 0.9, P = 0.007) and stronger belief in serious consequences (beta = 0.8, P = 0.008) increased depression. Levels of quality of life and distress were not impaired compared to the Dutch population. Illness and risk perception related variables were major determinants of quality of life and distress. Because these variables can be addressed and adjusted during pre- and post-test counseling, genetic counseling should focus on these determinants.

Hypertrophic cardiomyopathy is a common autosomal dominant disease, associated with heart failure and arrhythmias predisposing to sudden cardiac death. After the detection of the causal mutation in the proband predictive DNA testing of relatives is possible (cascade screening). Prevention of sudden cardiac death in patients with a high risk by means of an implantable cardioverter defibrillator is effective. In 97 hypertrophic cardiomyopathy families with a sarcomere gene mutation we retrospectively determined uptake of genetic counselling and predictive DNA testing in relatives within 1 year after the detection of the causal mutation in the proband. Uptake of genetic counselling was 39% and did not differ significantly by proband's or relative's gender, nor by young age of the relative (< 18 years) or a family history positive for sudden cardiac death. In second-degree relatives, eligible for predictive DNA testing when the first-degree relative had died, uptake was 27.5% (P = 0.047). Uptake of predictive genetic testing was 39%; conditional uptake of predictive genetic testing was 99%. Uptake of genetic counselling in hypertrophic cardiomyopathy is comparable to uptake in oncogenetics. Conditional uptake of predictive DNA testing, however, is much higher. Because sudden cardiac death can be prevented uptake of genetic counselling in hypertrophic cardiomyopathy should be as high as possible. To achieve this research into the determinants of uptake is needed.

Introduction: Developments in DNA-diagnostic techniques allow us to identify a significant proportion of patients with gene mutations causing familial heart diseass (arrhythmia syndromes, cardiomyopathies etc.) and to identify family members in early stages of the disease and/or even before symptoms occur. Early treatment can prevent sudden cardiac death and disease progression. However, data on long-term outcome in unselected genotyped patients are scarce due to a lack of large registries. In 2005, a national internet-based registry for familial heart diseases in the Netherlands, named GENCOR, was developed in collaboration with the Interuniversity Cardiology Institute of the Netherlands (ICIN)., Objectives: GENCOR aims to assess the prevalence of familial heart diseases in patients and families in the Netherlands and to facilitate research to improve the quality of diagnostics and therapy in familial heart diseases., Methods: Patients who visit the (cardio)genetic outpatient clinic are informed about GENCOR and asked to consent to the storage of information about cardiac examinations, family history and DNA diagnostics from all their visits. Patient data are entered into the internet-based GENCOR database by the cardiologist or clinical geneticist in attendance. Additional information can be stored for scientific research., Results: Four university hospitals are actively obtaining informed consent from the patients, which resulted in the inclusion of more than 300 patients. In 2006, more university hospitals will start using GENCOR and the aim is that all university hospitals will participate. Three research projects have already started using GENCOR., Conclusion: GENCOR is already a success, regarding the number of included patients and the related research projects set up within a limited period of time. GENCOR provides easy internet-based access for authorised cardiologists, clinical geneticists and scientists throughout the country.

A 38-year-old long-distance runner presented with pain in the left medial forefoot. In the presence of such symptoms, consideration should be given to a disease of or injury to a sesamoid bone. Radiology revealed a fracture line through the medial sesamoid bone under the first metatarsophalangeal joint. Conservative treatment was initially ineffective. Ultimately, local injections of lidocaine-methylprednisolone at the site of the pain, in the metatarsophalangeal joint and in the fracture line brought relief. In the diagnosis of patients with pain in the medial forefoot, apart from the patient's history and a physical examination, a skyline X-ray can be helpful to reveal a fractured or bipartite sesamoid. Almost all conditions affecting the sesamoids improve in the long run with conservative treatment. Besides reduction of weight-bearing pressure on the affected sesamoid, NSAIDs and ice massage, special attention should be paid to the foot (postural deformities), the shoe (inlays, sesamoid pad, shock absorption, stiff sole) and running on a soft surface. Insufficient therapeutic results may be due to osteonecrosis or non-union. These and persistent pain may, as a last resort, require surgical intervention such as screw fixation in case of a fracture or sesamoidectomy.

Objective: To acquire insight into the number and nature of claims for damages that were filed in the period 1993/'01 in hospitals insured by MediRisk and to compare this with the period 1980/'90., Design: Descriptive., Method: Data were collected from the registration system for insurance claims maintained by MediRisk, an insurer of medical liability risks. The data were processed up to and including 31 October 2002. There were 4058 claims in 3316 closed and 742 open dossiers. The results were compared with those from a comparable investigation into the period 1980/'90 (3970 claims; 1550 dossiers investigated). The number of invasive medical interventions in the period 1990-2001 was obtained from Prismant in Utrecht. Study of the dossiers yielded information about the use of legal procedures., Results: Compared to 1980/'90 there was a 34% increase in the number of claims for damages following medical interventions during the period 1993/'01. This increase was smaller than the growth in the number of high-risk interventions (47%). The percentage of rejected claims for damages was 6o in the period 1980/'90 and 68 in 1993/'01. In both periods, most of the claims pertained to surgical specialisms, in particular general surgery. In 370 of the 3316 closed dossiers (11%) a legal procedure was mentioned: complaints committee (5%; in 1980/'90 hospitals were not required to have a complaints committee), civil court (3%; this was 4% in 1980/'90) and the Medical Disciplinary Board (3%; this was 6% in 1980/'90)., Conclusion: The increase in the number of claims for damages filed against hospitals insured with MediRisk was limited compared to the number of medical interventions carried out. The number of legal procedures arising from these claims did rise in the absolute sense, but fell in relation to the number of claims for damages.