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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 Conclusions— Phospholamban R14del mutation carriers are at high risk for malignant ventricular arrhythmias and end-stage heart failure, with left ventricular ejection fraction

[Abstract] 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. Hôpitaux de Paris; PHRC AOM04141

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 from26 manifestHCMpatients (11 MYBPC3mut, 9MYH7mut, 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 [11C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging.Tension cost (TC), i.e.ATPase activity during force development, was higher in MYBPC3mut andMYH7mut compared with HCMsmn at saturating [Ca 2++]. TC was also significantly higher in MYH7mut at submaximal, more physiological [Ca2++]. 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. © The Author 2014.

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

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.

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’.

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease. A recent study showed that male KLF10-encoded TGF beta 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. J. Cell. Biochem. 113: 18961903, 2012. (C) 2012 Wiley Periodicals, Inc

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.

In this part of a series on founder mutations in the Netherlands, we review familial idiopathic ventricular fibrillation linked to the DPP6 gene. Familial idiopathic ventricular fibrillation determines an intriguing subset of the inheritable arrhythmia syndromes as there is no recognisable phenotype during cardiological investigation other than ventricular arrhythmias highly associated with sudden cardiac death. Until recently, it was impossible to identify presymptomatic family members at risk for fatal events. We uncovered several genealogically linked families affected by numerous sudden cardiac deaths over the past centuries, attributed to familial idiopathic ventricular fibrillation. Notably, ventricular fibrillation in these families was provoked by very short coupled monomorphic extrasystoles. We were able to associate their phenotype of lethal arrhythmic events with a haplotype harbouring the DPP6 gene. While this gene has not earlier been related to cardiac arrhythmias, we are now able, for the first time, to identify and to offer timely treatment to presymptomatic family members at risk for future fatal events solely by genetic analysis. Therefore, when there is a familial history of unexplained sudden cardiac deaths, a link to the DPP6 gene may be explored as it may enable risk evaluation of the remaining family members. In addition, when closely coupled extrasystoles initiate ventricular fibrillation in the absence of other identifiable causes, a link to the DPP6 gene should be suspected.

The goal of this study was to assess the mortality of hypertrophic cardiomyopathy (HCM), partly in times when the disease was not elucidated and patients were untreated.HCM is feared for the risk of sudden cardiac death (SCD). Insight in the natural history of the disorder is needed to design proper screening strategies for families with HCM.In 6 large, 200-year multigenerational pedigrees (identified by using genealogical searches) and in 140 small (contemporary) pedigrees (first-degree relatives of the proband) with HCM caused by a truncating mutation in the myosin-binding protein C gene (n = 1,118), we determined all-cause mortality using the family tree mortality ratio method. The study's main outcome measure was the standardized mortality ratio (SMR).In the large pedigrees, overall mortality was not increased (SMR 0.86 [95% confidence interval (CI): 0.72 to 1.03]), but significant excess mortality occurred between 10 and 19 years (SMR 2.7 [95% CI: 1.2 to 5.2]). In the small families, the SMR was increased (SMR 1.5 [95% CI: 1.3 to 1.6]) [corrected] and excess mortality was observed between 10 and 39 years (SMR 3.2 [95% CI: 2.3 to 4.3]) and 50 and 59 years (SMR 1.9 [95% CI: 1.4 to 2.5]).We identified specific age categories with increased mortality risks in HCM families. The small, referred pedigrees had higher mortality risks than the large 200-year multigenerational pedigrees. Our findings support the strategy of starting cardiological and genetic screening in the first-degree relatives of a proband from 10 years onward and including persons in the screening at least until the age of 60 years. Screening of more distant relatives is probably most efficient between 10 and 19 years.

1.2 OMIM# of the disease 192600 Cardiomyopathy, familial hypertrophic; CMH. 115195 Cardiomyopathy, familial hypertrophic, 2; CMH2. 115196 Cardiomyopathy, familial hypertrophic, 3; CMH3. 115197 Cardiomyopathy, familial hypertrophic, 4; CMH4. 600858 Cardiomyopathy, familial hypertrophic, 6; CMH6. +191044 Cardiomyopathy, familial hypertrophic, 7; CMH7. 608751 Cardiomyopathy, familial hypertrophic, 8; CMH8. +191044 Cardiomyopathy, familial hypertrophic, 9; CMH9. 608758 Cardiomyopathy, familial hypertrophic, 10; CMH10. 612098 Cardiomyopathy, familial hypertrophic, 11; CMH11. 612124 Cardiomyopathy, familial hypertrophic, 12; CMH12. 613243 Cardiomyopathy, familial hypertrophic, 13; CMH13. 613251 Cardiomyopathy, familial hypertrophic, 14; CMH14. 613243 Cardiomyopathy, familial hypertrophic, 15; CMH15.

Item does not contain fulltext AIMS: We investigated the presence of a clinical diagnosis of hypertrophic cardiomyopathy (HCM), risk factors for sudden cardiac death (SCD), and cardiac events during follow-up in predictively tested-not known to have a clinical diagnosis of HCM before the DNA test-carriers of a sarcomeric gene mutation and associations with age and gender to determine the best cardiological screening strategy. METHODS AND RESULTS: One hundred and thirty-six (30%) of 446 mutation carriers were diagnosed with HCM at one or more cardiological evaluation(s). Male gender and higher age were associated with manifest disease. Incidence of newly diagnosed manifest HCM was 10% in older carriers, although numbers were small in carriers /=2 risk factors and manifest HCM) was present in 17 carriers during follow-up (2.4% per person-year). Age but not gender was associated with a high-risk status for SCD. CONCLUSION: Thirty percent of carriers had or developed manifest HCM after predictive DNA testing and risk factors for SCD were frequently present. Our data suggest that the SCD risk is low and risk stratification for SCD can be omitted in carriers without manifest disease and that frequency of cardiological evaluations can possibly be decreased in carriers between 15 and 40 years as long as hypertrophy is absent.

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 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.

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.

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.

To the Editor We have read the paper on hypertrophic cardiomyopathy (HCM) by ten Berg et al with great interest.1 As the paper has an educational aim, we would like to address some minor misconceptions that could have major implications. Genotyping in HCM to establish a molecular diagnosis in HCM patients can indeed probably not be used to guide prognosis or therapy. However, it has …

Objective: The aim of this study was to identify the genetic defect underlying the combined clinical presentation of bradycardia and left ventricular noncompaction cardiomyopathy (LVNC), hypothesizing that these two clinical abnormalities have a common genetic cause. Background: Familial forms of primary sinus bradycardia have in some cases 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 LVNC pointing to a shared genetic cause. Methods: Exome sequencing was carried out in two 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 five affected family members that were identified using SNP-array analysis. Results: The combined linkage analysis and exome sequencing in the index family identified 11 novel variants shared among the two affected cousins. One of these, p.G482R in HCN4, segregated with the combined bradycardia and LVNC phenotype in the entire family. Subsequent screening of HCN4 in three additional families, with the same clinical combination of bradycardia and LVNC, identified HCN4 mutations in all three. In electrophysiological studies, all found HCN4 mutations showed a more negative voltage-dependency of activation, consistent with the observed bradycardia. Conclusions: While mutations in HCN4 have been previously linked to bradycardia, our study provides the first evidence that mutations in this ion channel gene may also associate with structural abnormalities of the myocardium.

Purpose: Idiopathic ventricular fibrillation (IVF) is a rare but notoriously difficult to manage arrhythmia syndrome as there are no clinical identifiers to establish the risk for a premature cardiac arrest. However, we recently uncovered a link between familial IVF and a risk haplotype on the new arrhythmia gene DPP6 on chromosome 7q36 in several related IVF families. DPP6 is putatively involved in the Ito current in heart. In this study we characterise both the extended bench and bedside evaluations in IVF linked to DPP6. Methods: We studied 235 carriers and 267 non-carriers of the DPP6 risk haplotype. Clinical parameters and a combination of all cause mortality and cardiac arrest were evaluated. Additional expression studies in human cardiac tissue samples and adenovirus-mediated gene transfer studies in cultured canine Purkinje cells and cardiomyocytes were performed. Results: Successfully resuscitated patients did not have any sign of other inheritable arrhythmia syndromes. Recorded IVF was always initiated by monomorphic short-coupled extrasystoles from the right ventricular apex/lower free wall. Ablation of extrasystole preceding Purkinje potentials and/or the administration quinidine led to suppression of subsequent arrhythmias. Carriers and non-carriers had normal and similar electrocardiographic and echocardiographic indices. Cardiac MRI showed a trend to slightly larger right ventricular volumes in carriers, but these were still within normal limits and not clinically useful. Death and/or cardiac arrest occurred in 84 carriers and 10 non-carriers. Median survival of carriers was 68 years (p

Background: Until recently it was impossible to identify presymptomatic family members at risk for fatal events in familial idiopathic ventricular fibrillation (IVF). We uncovered a large IVF-family and linked their arrhythmic events to a new arrhythmia gene on chromosome 7q36: DPP6. Methods and Results: We studied 169 carriers and 195 non-carriers. ECGs and echocardiography were normal. All-cause mortality or IVF/resuscitation occurred in 67 carriers and 7 non-carriers (no IVF/resuscitation). At 62 years of age, 50% of carriers had an event (p

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.

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.Descriptive.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.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).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.

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).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.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.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.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.