Circulating Acylcarnitines Associated with Hypertrophic Cardiomyopathy Severity: an Exploratory Cross-Sectional Study in MYBPC3 Founder Variant Carriers.

Hypertrophic cardiomyopathy (HCM) is a relatively common genetic heart disease characterised by myocardial hypertrophy. HCM can cause outflow tract obstruction, sudden cardiac death and heart failure, but severity is highly variable. In this exploratory cross-sectional study, circulating acylcarnitines were assessed as potential biomarkers in 124 MYBPC3 founder variant carriers (59 with severe HCM, 26 with mild HCM and 39 phenotype-negative [G + P-]). Elastic net logistic regression identified eight acylcarnitines associated with HCM severity. C3, C4, C6-DC, C8:1, C16, C18 and C18:2 were significantly increased in severe HCM compared to G + P-, and C3, C6-DC, C8:1 and C18 in mild HCM compared to G + P-. In multivariable linear regression, C6-DC and C8:1 correlated to log-transformed maximum wall thickness (coefficient 5.01, p = 0.005 and coefficient 0.803, p = 0.007, respectively), and C6-DC to log-transformed ejection fraction (coefficient -2.50, p = 0.004). Acylcarnitines seem promising biomarkers for HCM severity, however prospective studies are required to determine their prognostic value.

BIO FOr CARE: biomarkers of hypertrophic cardiomyopathy development and progression in carriers of Dutch founder truncating MYBPC3 variants-design and status.

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.

Risk stratification and subclinical phenotyping of dilated and/or arrhythmogenic cardiomyopathy mutation-positive relatives: CVON eDETECT consortium.

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.

How to inform relatives at risk of hereditary diseases? A mixed-methods systematic review on patient attitudes.

When a genetic disease-causing variant causing autosomal dominant diseases is identified, predictive DNA testing is possible for at-risk relatives to investigate whether they are carrying the familial variant. In current practice, the proband is asked to inform at-risk relatives, often supported by a family letter. This review summarizes the literature on preferences of probands and relatives regarding how and by whom at-risk relatives should be informed. A search involving digital databases (Pubmed, Medline, and PsycInfo) focusing on patient attitudes toward informing relatives at risk of autosomal dominant onco-, cardio-, or neurogenetic disease, resulted in 1,431 screened records, of which 117 full-text papers were assessed. Eventually, 32 studies were selected. This review shows that a majority of participants was in favor of someone in the family to inform their at-risk relatives, with participants generally feeling responsible for informing relatives at risk themselves. However, variation in patient preferences regarding who should inform was observed. Face-to-face disclosure by the proband with additional information material for relatives provided by HCPs was most appreciated. Actively offered support of healthcare professionals was desired. In conclusion, although the family-mediated approach was appreciated by a majority of participants, support by healthcare professionals was desired. By taking patient attitudes into account, the approach used to inform at-risk relatives could be improved. Subsequently, more relatives will be informed and enabled to attend genetic counseling and make an informed decision regarding predictive DNA testing. Further research on patient attitudes, specifying for disease type and cultural background, is needed.

Large next-generation sequencing gene panels in genetic heart disease: challenges in clinical practice.

BACKGROUND: Next-generation sequencing gene panels are increasingly used for genetic diagnosis in inherited cardiac diseases. Besides pathogenic variants, multiple variants, variants of uncertain significance (VUS) and incidental findings can be detected. Such test results can be challenging for counselling and clinical decision making. METHODS: We present patient cases to illustrate the challenges that can arise when unclear genetic test results are detected in cardiogenetic gene panels. RESULTS: We identified three types of challenging gene panel results: 1) one or more VUS in combination with a pathogenic variant, 2) variants associated with another genetic heart disease, and 3) variants associated with a syndrome involving cardiac features. CONCLUSION: Large gene panels not only increase the detection rates of pathogenic variants but also of variants with uncertain pathogenicity, multiple variants and incidental findings. Gene panel results can be challenging for genetic counselling and require proper pre-test and post-test counselling. We advise evaluation of challenging cases by a multidisciplinary team.

Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.

BACKGROUND: Genetic heterogeneity is common in inherited cardiac diseases. Next-generation sequencing gene panels are therefore suitable for genetic diagnosis. We describe the results of implementation of cardiomyopathy and arrhythmia gene panels in clinical care. METHODS: We present detection rates for variants with unknown (class 3), likely (class 4), and certain (class 5) pathogenicity in cardiogenetic gene panels since their introduction into diagnostics. RESULTS: In 936 patients tested on the arrhythmia panel, likely pathogenic and pathogenic variants were detected in 8.8% (4.6% class 5; 4.2% class 4), and one or multiple class 3 variants in 34.8%. In 1970 patients tested on the cardiomyopathy panel, likely pathogenic and pathogenic variants were detected in 19.8% (12.0% class 5; 7.9% class 4), and one or multiple class 3 variants in 40.8%. Detection rates of all different classes of variants increased with the increasing number of genes on the cardiomyopathy gene panel. Multiple variants were detected in 11.7% and 28.5% of patients on the arrhythmia and cardiomyopathy panels respectively. In more recent larger versions of the cardiomyopathy gene panel the detection rate of likely pathogenic and pathogenic variants only slightly increased, but was associated with a large increase of class 3 variants. CONCLUSION: Overall detection rates (class 3, 4, and 5 variants) in a diagnostic setting are 44% and 61% for the arrhythmia and cardiomyopathy gene panel respectively, with only a small minority of likely pathogenic and pathogenic variants (8.8% and 19.8% respectively). Larger gene panels can increase the detection rate of likely pathogenic and pathogenic variants, but mainly increase the frequency of variants of unknown pathogenicity.

Founder mutations in the Netherlands: familial idiopathic ventricular fibrillation and DPP6.

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.

Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas.

BACKGROUND: Multiple meningiomas occur in <10% of meningioma patients. Their development may be caused by the presence of a predisposing germline mutation in the neurofibromatosis type 2 (NF2) gene. The predisposing gene in patients with non-NF2 associated multiple meningiomas remains to be identified. Recently, SMARCB1 was reported to be a potential predisposing gene for multiple meningiomas in a family with schwannomatosis and multiple meningiomas. However, involvement of this gene in the development of the meningiomas was not demonstrated. RESULTS: Five affected members of a large family with multiple meningiomas were investigated for the presence of mutations in SMARCB1 and NF2. A missense mutation was identified in exon 2 of SMARCB1 as the causative germline mutation predisposing to multiple meningiomas; furthermore, it was demonstrated that, in accordance with the two-hit hypothesis for tumourigenesis, the mutant allele was retained and the wild-type allele lost in all four investigated meningiomas. In addition, independent somatically acquired NF2 mutations were identified in two meningiomas of one patient with concomitant losses of the wild-type NF2 allele. CONCLUSION: It is concluded that, analogous to the genetic events in a subset of schwannomatosis associated schwannomas, a four-hit mechanism of tumour suppressor gene inactivation, involving SMARCB1 and NF2, might be operative in familial multiple meningiomas associated meningiomas.

Founder mutations in hypertrophic cardiomyopathy patients in the Netherlands.

In this part of a series on cardiogenetic founder mutations in the Netherlands, we review the Dutch founder mutations in hypertrophic cardiomyopathy (HCM) patients. HCM is a common autosomal dominant genetic disease affecting at least one in 500 persons in the general population. Worldwide, most mutations in HCM patients are identified in genes encoding sarcomeric proteins, mainly in the myosin-binding protein C gene (MYBPC3, OMIM #600958) and the beta myosin heavy chain gene (MYH7, OMIM #160760). In the Netherlands, the great majority of mutations occur in the MYBPC3, involving mainly three Dutch founder mutations in the MYBPC3 gene, the c.2373_2374insG, the c.2864_2865delCT and the c.2827C>T mutation. In this review, we describe the genetics of HCM, the genotype-phenotype relation of Dutch founder MYBPC3 gene mutations, the prevalence and the geographic distribution of the Dutch founder mutations, and the consequences for genetic counselling and testing. (Neth Heart J 2010;18:248-54.).

Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy: Dutch cardiologists and the care of mutation carriers.

Background. Patients with hypertrophic cardiomyopathy (HCM) and HCM mutation carriers are at risk of sudden cardiac death (SCD). Both groups should therefore be subject to regular cardiological testing - including risk stratification for SCD - according to international guidelines. We evaluated Dutch cardiologists' knowledge of and adherence to international guidelines on risk stratification and prevention of SCD in mutation carriers with and without manifest HCM.Methods. A questionnaire was sent to 1109 Dutch cardiologists (in training) containing case-based questions.Results. The response rate was 21%. Own general knowledge on HCM care was rated as insufficient by 63% of cardiologists. The percentage of correct answers (i.e. in agreement with international guidelines), on the case-based questions ranged from 37 to 96%, being lowest in cases with an unknown number of risk factors for SCD. A substantial portion of correct answers was based on the correct answer 'ask an expert opinion'. Significantly more correct answers were provided in cases with manifest HCM. There was little difference between the answers of cardiologists with different self-reported levels of knowledge, with different numbers of HCM patients in their practice or with different numbers of carriers without manifest HCM.Conclusion. Knowledge on risk stratification and preventive therapy was mediocre, and knowledge gaps exist, especially on HCM mutation carriers without manifest disease. Fortunately, experts are frequently asked for their opinion which might bring patient care to an adequate level. Hopefully, our results will stimulate cardiologists to follow developments in this field, thereby increasing quality of care for HCM patients and mutation carriers. (Neth Heart J 2009;17:464-9.).

ESCAPE-HCM study: Evaluation of SCreening of Asymptomatic PatiEnts with Hypertrophic CardioMyopathy.

The ESCAPE-HCM study is a prospective followup study of asymptomatic mutation-carrying relatives of HCM patients aiming at optimising anamnestic and cardiological evaluation and surveillance for this group. All relatives undergo regular cardiological evaluation and risk status is prospectively estimated, according to known HCM-related risk factors for sudden cardiac death. (Neth Heart J 2007;15:216-20.).

GENCOR: a national registry for patients and families suffering from a familial heart disease in the Netherlands.

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 long-distance runner with a painful sesamoid bone in the forefoot]. / Een duurloper met een pijnlijk sesambeentje in de voorvoet.

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.

[No spectacular rise in claims for medical damages in The Netherlands: 1993-'01 compared to 1980-'90]. / Geen spectaculaire ontwikkeling van medische schadeclaims in Nederland: 1993/'01 in vergelijking met 1980/'90.

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.