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

A Dutch MYH7 founder mutation, p.(Asn1918Lys), is associated with early onset cardiomyopathy and congenital heart defects

Background Mutations in the myosin heavy chain 7 (MYH7) gene commonly cause cardiomyopathy but are less frequently associated with congenital heart defects. Methods In th

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

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 detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype–phenotype correlations based on available evidence

Systematic Review of Genotype-Phenotype Correlations in Noncompaction Cardiomyopathy

Background A genetic cause can be identified in 30% of noncompaction cardiomyopathy patients (NCCM) with clinical features ranging from asymptomatic cardiomyopathy to heart failure with major adverse cardiac events (MACE). Methods and Results To investigate genotype-phenotype correlations, the genotypes and clinical features of genetic NCCM patients were collected from the literature. We compared age at diagnosis, cardiac features and risk for MACE according to mode of inheritance and molecular effects for defects in the most common sarcomere genes and NCCM subtypes. Geno- and phenotypes of 561 NCCM patients from 172 studies showed increased risk in children for congenital heart defects (P<0.001) and MACE (P<0.001). In adult NCCM patients the main causes were single missense mutations in sarcomere genes. Children more frequently had an X-linked or mitochondrial inherited defect (P=0.001) or chromosomal anomalies (P<0.001). MYH7 was involved in 48% of the sarcomere gene mutations. MYH7 and ACTC1 mutations had lower risk for MACE than MYBPC3 and TTN (P=0.001). The NCCM/dilated cardiomyopathy cardiac phenotype was the most frequent subtype (56%; P=0.022) and was associated with an increased risk for MACE and high risk for left ventricular systolic dysfunction (<0.001). In multivariate binary logistic regression analysis MYBPC3, TTN, arrhythmia -, non-sarcomere non-arrhythmia cardiomyopathy-and X-linked genes were genetic predictors for MACE. Conclusions Sarcomere gene mutations were the most common cause in adult patients with lower risk of MACE. Children had multi-systemic disorders with severe outcome, suggesting that the diagnostic and clinical approaches should be adjusted to age at presentation. The observed genotype-phenotype correlations endorsed that DNA diagnostics for NCCM is important for clinical management and counseling of patients

State-of-the art review: Noncompaction cardiomyopathy in pediatric patients

Noncompaction cardiomyopathy (NCCM) is a disease characterized by hypertrabeculation, commonly hypothesized due to an arrest in compaction during fetal development. In 2006, NCCM was classified as a distinct form of cardiomyopathy (CMP) by the American Heart Association. NCCM in childhood is more frequently familial than when diagnosed in adulthood and is associated with other congenital heart diseases (CHDs), other genetic CMPs, and neuromuscular diseases (NMDs). It is yet a rare cardiac diseased with an estimated incidence of 0.12 per 100.000 in children up to 10 years of age. Diagnosing NCCM can be challenging due to non-uniform diagnostic criteria, unawareness, presumed other CMPs, and presence of CHD. Therefore, the incidence of NCCM in children might be an underestimation. Nonetheless, NCCM is the third most common cardiomyopathy in childhood and is associated with heart failure, arrhythmias, and/or thromboembolic events. This state-of-the-art review provides an overview on pediatric NCCM. In addition, we discuss the natural history, epidemiology, genetics, clinical presentation, outcome, and therapeutic options of NCCM in pediatric patients, including fetuses, neonates, infants, and children. Furthermore, we provide a simple classification of different forms of the disease. Finally, the differences between the pediatric population and the adult population are described

Diagnostic Cardiovascular Magnetic Resonance Imaging Criteria in Noncompaction Cardiomyopathy and the Yield of Genetic Testing

Background Noncompaction cardiomyopathy (NCCM) is characterized by a thickened myocardial wall with excessive trabeculations of the left ventricle, and ∼30% is explained by a (likely) pathogenic variant [(L)PV] in a cardiomyopathy gene. Diagnosing an (L)PV is important because it allows accurate identification of which relatives are at risk and helps predicting prognosis. The goal of this study was to assess which specific clinical and morphologic characteristics of the myocardium may predict an (L)PV and which of the cardiovascular magnetic resonance (CMR) diagnostic criteria for NCCM can best be used for that purpose. Methods Sixty-two patients with NCCM, diagnosed by means of echocardiographic Jenni criteria, underwent CMR imaging that was evaluated according the Petersen, Stacey, Jacquier, Captur, and Choi diagnostic CMR criteria for NCCM. Patients also underwent DNA testing and were stratified according to having an (L)PV. Results Thirty-three patients (53%) with NCCM had an (L)PV. The apical and mid-lateral segments were the dominant locations for meeting Petersen and/or Stacey criteria. Correlation between different CMR criteria varied from moderate to very strong. In multivariate binary logistic regression analysis with CMR and non-CMR parameters, independent positive predictors for an (L)PV were familial cardiomyopathy, trabecular mass, and meeting Petersen criteria in ≥ 2 out of 3 long-axis views, whereas left bundle branch block and hypertension were negative predictors. The receiver operating characteristic curve of this multivariate model had an area under the curve of 0.89 (95% confidence interval 0.82-0.97). Conclusions CMR criteria together with family history help to distinguish those patients in whom an (L)PV can be identified, consequently leading to referral for genetic diagnostics and cascade screening

Cardiac Phenotypes, Genetics, and Risks in Familial Noncompaction Cardiomyopathy

BACKGROUND There is overlap in genetic causes and cardiac features in noncompaction cardiomyopathy (NCCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM). OBJECTIVES The goal of this study was to predict phenotype and outcome in relatives according to the clinical features and genotype of NCCM index cases. METHODS Retrospective DNA and cardiac screening of relatives of 113 families from 143 index patients were used to classify NCCM cases according to the cardiac phenotype. These cases were classified as isolated NCCM, NCCM with left ventricular (LV) dilation (DCM), and NCCM with LV hypertrophy (HCM). RESULTS In 58 (51%) families, screening identified 73 relatives with NCCM and 34 with DCM or HCM without NCCM. The yield of family screening was higher in families with a mutation (p <0.001). Fifty-four families had a mutation. Nonpenetrance was observed in 37% of the relatives with a mutation. Index cases were more often symptomatic than affected relatives (p <0.001). NCCM with DCM (53%) was associated with LV systolic dysfunction (p <0.001), increased risk for major adverse cardiac events, mutations in the tail of MYH7 (p <0.001), and DCM without NCCM in relatives (p <0.001). Isolated NCCM (43%) was associated with a milder course, mutations in the head of MYH7, asymptomatic NCCM (42%) (p = 0.018), and isolated NCCM in relatives (p = 0.004). NCCM with HCM (4%) was associated with MYBPC3 and HCM without NCCM in relatives (p <0.001). CONCLUSIONS The phenotype of relatives may be predicted according to the NCCM phenotype and the mutation of index patients. NCCM phenotypes were related to outcome. In this way, clinical and genetic features of index patients may help prediction of outcome in relatives. (C) 2019 by the American College of Cardiology Foundation