👤 Danielle Majoor-Krakauer

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 ( Show less

There is overlap in genetic causes and cardiac features in noncompaction cardiomyopathy (NCCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM). The goal of this study was to predict phenotype and outcome in relatives according to the clinical features and genotype of NCCM index cases. 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). 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). 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. Show less

The clinical outcomes of noncompaction cardiomyopathy (NCCM) range from asymptomatic to heart failure, arrhythmias, and sudden cardiac death. Genetics play an important role in NCCM. This study investigated the correlations among genetics, clinical features, and outcomes in adults and children diagnosed with NCCM. A retrospective multicenter study from 4 cardiogenetic centers in the Netherlands classified 327 unrelated NCCM patients into 3 categories: 1) genetic, with a mutation in 32% (81 adults; 23 children) of patients; 2) probably genetic, familial cardiomyopathy without a mutation in 16% (45 adults; 8 children) of patients; or 3) sporadic, no family history, without mutation in 52% (149 adults; 21 children) of patients. Clinical features and major adverse cardiac events (MACE) during follow-up were compared across the children and adults. MYH7, MYBPC3, and TTN mutations were the most common mutations (71%) found in genetic NCCM. The risk of having reduced left ventricular (LV) systolic dysfunction was higher for genetic patients compared with the probably genetic and sporadic cases (p = 0.024), with the highest risk in patients with multiple mutations and TTN mutations. Mutations were more frequent in children (p = 0.04) and were associated with MACE (p = 0.025). Adults were more likely to have sporadic NCCM. High risk for cardiac events in children and adults was related to LV systolic dysfunction in mutation carriers, but not in sporadic cases. Patients with MYH7 mutations had low risk for MACE (p = 0.03). NCCM is a heterogeneous condition, and genetic stratification has a role in clinical care. Distinguishing genetic from nongenetic NCCM complements prediction of outcome and may lead to management and follow-up tailored to genetic status. Show less

Hypertrophic Cardiomyopathy (HCM) is a genetically heterogeneous disease. One specific mutation in the MYBPC3 gene is highly prevalent in center east of France giving an opportunity to define the clinical profile of this specific mutation. HCM probands were screened for mutation in the MYH7, MYBPC3, TNNT2 and TNNI3 genes. Carriers of the MYBPC3 IVS20-2A>G mutation were genotyped with 8 microsatellites flanking this gene. The age of this MYBPC3 mutation was inferred with the software ESTIAGE. The age at first symptom, diagnosis, first complication, first severe complication and the rate of sudden death were compared between carriers of the IVS20-2 mutation (group A) and carriers of all other mutations (group B) using time to event curves and log rank test. Out of 107 HCM probands, 45 had a single heterozygous mutation in one of the 4 tested sarcomeric genes including 9 patients with the MYBPC3 IVS20-2A>G mutation. The IVS20-2 mutation in these 9 patients and their 25 mutation carrier relatives was embedded in a common haplotype defined after genotyping 4 polymorphic markers on each side of the MYBPC3 gene. This result supports the hypothesis of a common ancestor. Furthermore, we evaluated that the mutation occurred about 47 generations ago, approximately at the 10th century.We then compared the clinical profile of the IVS20-2 mutation carriers (group A) and the carriers of all other mutations (group B). Age at onset of symptoms was similar in the 34 group A cases and the 73 group B cases but group A cases were diagnosed on average 15 years later (log rank test p = 0.022). Age of first complication and first severe complication was delayed in group A vs group B cases but the prevalence of sudden death and age at death was similar in both groups. A founder mutation arising at about the 10th century in the MYBPC3 gene accounts for 8.4% of all HCM in center east France and results in a cardiomyopathy starting late and evolving slowly but with an apparent risk of sudden death similar to other sarcomeric mutations. Show less

The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P=0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM. Show less

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.2373₂₃₇₄insG, the c.2864₂₈₆₅delCT 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.). Show less

To investigate the outcome of cardiac evaluation and the risk stratification for sudden cardiac death (SCD) in asymptomatic hypertrophic cardiomyopathy (HCM) mutation carriers. Seventy-six HCM mutation carriers from 32 families identified by predictive DNA testing underwent cardiac evaluation including history, examination, electrocardiography, Doppler echocardiography, exercise testing, and 24 h Holter monitoring. The published diagnostic criteria for HCM in adult members of affected families were used to diagnose HCM. Thirty-three (43%) men and 43 (57%) women with a mean age of 42 years (range 16-79) were examined; in 31 (41%) HCM was diagnosed. Disease penetrance was age related and men were more often affected than women (P = 0.04). Myosin Binding Protein C (MYBPC3) mutation carriers were affected at higher age than Myosin Heavy Chain (MYH7) mutation carriers (P = 0.01). Risk factors for SCD were present in affected and unaffected carriers. Hypertrophic cardiomyopathy was diagnosed in 41% of carriers. Disease penetrance was age dependent, warranting repeated cardiologic evaluation. The MYBPC3 mutation carriers were affected at higher age than MYH7 mutation carriers. Risk factors for SCD were present in carriers with and without HCM. Follow-up studies are necessary to evaluate the effectiveness of risk stratification for SCD in this population. Show less

To test the hypothesis that carriers of Dutch founder mutations in cardiac myosin-binding protein C (MYBPC3), without left ventricular hypertrophy (LVH) or electrocardiographic abnormalities, have diastolic dysfunction on tissue Doppler imaging (TDI), which can be used for the screening of family members in the hypertrophic cardiomyopathy (HCM) population. TDI is a more sensitive technique for the assessment of left ventricular contraction and relaxation abnormalities than is conventional echocardiography. Echocardiographic studies including TDI were performed in genotyped hypertrophic cardiomyopathy patients (genotype-positive, G+/LVH+; n = 27), mutation carriers without LVH (G+/LVH-; n = 27), and healthy controls (n = 55). The identified mutations in MYBPC3 in the G+/LVH+ subjects were c.2864₂₈₆₅delCT (12 subjects), c.2373dupG (n = 8), and p. Arg943X (n = 7). In the G+/LVH- subjects, the following mutations were identified: c.2864₂₈₆₅delCT (n = 11), c.2373dupG (n = 8), and p. Arg943X (n = 8). Mean TDI-derived systolic and early and late diastolic mitral annular velocities were significantly lower in the G+/LVH+ subjects compared with the other groups. However, there was no difference between controls and G+/LVH- subjects. Mean TDI-derived late mitral annular diastolic velocities were significantly higher in the G+/LVH- subjects compared with controls and G+/LVH+ subjects. Using a cut-off value of mean +/- 2 SD, an abnormal late mitral annular diastolic velocity was found in 14 (51%) of G+/LVH- patients. There was no difference among the 3 different mutations. In contrast to earlier reports, mean mitral annular systolic velocity and early mitral annular diastolic velocity velocities were not reduced in G+/LVH- subjects, and TDI velocities were not sufficiently sensitive for determination of the affected status of an individual subject. Our findings, however, support the theory that diastolic dysfunction is a primary component of pre-clinical HCM. Show less