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.
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.
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.
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.
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.
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.
Graphical abstract
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.
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.
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.
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.
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.
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.
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.
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.).
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