Genetic Aspects and Family Studies of Noncompaction and Hypertrophic Cardiomyopathy

The first reports of familial cardiac disorders appeared over 60 years ago. Since then, knowledge on cardiogenetic disorders has increased tremendously. And now cardiogenetics is a rapidly expanding field, including the familial cardiomyopathies, arrhythmias, congenital heart diseases and cardiovascular disorders. Most of these disorders have an autosomal dominant inheritance pattern. In the last decade many genes involved in these disorders have been identified and more discoveries are sure to follow. The growing insight in the genetic conditions of the cardiovascular system has led to a substantial increase in the number of patients referred to clinical genetic departments for genetic counselling and DNA diagnostics. Close collaboration of departments of cardiology and genetics resulted in the initiation of m

FLNC missense variants in familial noncompaction cardiomyopathy

The majority of familial noncompaction cardiomyopathy (NCCM) is explained by pathogenic variants in the same sarcomeric genes that are associated with hypertrophic (HCM) and dilated (DCM) cardiomyopathy. Pathogenic variants in the filamin C gene (FLNC) have been linked to HCM and DCM. We expand the spectrum of FLNC related cardiomyopathies by presenting two families with likely pathogenic FLNC variants showing familial segregation of NCCM and concurrent coarctation of the aorta and/or mitral valve abnormalities

The first titin (c.59926+1G > A) founder mutation associated with dilated cardiomyopathy

Cardiolog

A mutation update for the FLNC gene in myopathies and cardiomyopathies

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrim

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

Hypotriploidy 68,XX: a new case report and review of earlier cases.

Item does not contain fulltextWe report a prematurely born patient with a 68,XX karyotype. She presented with syndactyly of 2nd and 3rd toes, minor facial features, microcephaly, slender hands, bicuspid aortic valve, patent ductus arteriosus and hypotonia. Comparison with other reported cases is given

Hypotriploidy 68,XX: a new case report and review of earlier cases.

We report a prematurely born patient with a 68,XX karyotype. She presented with syndactyly of 2nd and 3rd toes, minor facial features, microcephaly, slender hands, bicuspid aortic valve, patent ductus arteriosus and hypotonia. Comparison with other reported cases is given

Familial screening and genetic counselling in hypertrophic cardiomyopathy: the Rotterdam experience

Hypertrophic cardiomyopathy (HCM) is a disease characterised by unexplained left ventricular hypertrophy (LVH) (i.e. LVH in the absence of another cardiac or systemic disease that could produce a similar degree of hypertrophy), electrical instability and sudden death (SD)

A tailored approach to informing relatives at risk of inherited cardiac conditions: results of a randomised controlled trial

If undetected, inherited cardiac conditions can lead to sudden cardiac death, while treatment options are available. Predictive DNA testing is therefore advised for at-risk relatives, and probands are currently asked to inform relatives about this. However, fewer than half of relatives attend genetic counselling. In this trial, we compared a tailored approach to informing relatives, in which probands were asked whether they preferred relatives to be informed by themselves or by the genetic counsellor, with current practice. Our primary outcome was uptake of genetic counselling in relatives in the first year after test result disclosure. Secondary outcomes were evaluation of the approach and impact on psychological/family functioning measured 3 (T1) and 9 (T2) months post-disclosure via telephone interviews and questionnaires. We included 96 probands; 482 relatives were eligible for counselling and genetic testing. We observed no significant difference in uptake of genetic counselling between the control (38%) and the intervention (37%) group (p = 0.973). Nor were there significant differences between groups in impact on family/psychological functioning. Significantly more probands in the tailored group were satisfied (p = 0.001) and felt supported (p = 0.003) by the approach, although they also felt somewhat coerced to inform relatives (p < 0.001) and perceived room for improvement (p < 0.001). To conclude, we observed no differences in uptake and impact on family/psychological functioning between the current and tailored approach, but probands in the tailored group more often felt satisfied. Further research on barriers to relatives attending genetic counselling and on how to optimize the provision of a tailored approach is needed

Screening, diagnosis and follow-up of Brugada syndrome in children: a Dutch expert consensus statement

Brugada syndrome (BrS) is a rare inherited arrhythmia syndrome. Affected children may experience life-threatening symptoms, mainly during fever. The percentage of SCN5A variant carriers in children is higher than in adults. Current diagnostic and follow-up policies for children with (a family history of) BrS vary between centres. Here, we present a consensus statement based on the current literature and expert opinions to standardise the approach for all children with BrS and those from BrS families in the Netherlands. In summary, BrS is diagnosed in patients with a spontaneous type 1 electrocardiogram (ECG) pattern or with a Shanghai score >= 3.5 including >= 1 ECG finding. A sodium channel-blocking drug challenge test should only be performed after puberty with a few exceptions. A fever ECG is indicated in children with suspected BrS, in children with a first-degree family member with definite or possible BrS according to the Shanghai criteria with a SCN5A variant and in paediatric SCN5A variant carriers. In-hospital rhythm monitoring during fever is indicated in patients with an existing type 1 ECG pattern and in those who develop such a pattern. Genetic testing should be restricted to SCN5A. Children with BrS and children who carry an SCN5A variant should avoid medication listed at and fever should be suppressed. Ventricular arrhythmias or electrical storms should be treated with isoproterenol infusion