Genetic Determinants Of Clinical Phenotype In Hypertrophic Cardiomyopathy

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identified mutations.Methods: As a part of the international multidisciplinary SILICOFCM project (www.silicofcm.eu) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography.Results: The most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p=0.014). There was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p=0.085). Laboratory analyses revealed normal levels of creatinine (85.5±18.3 vs. 81.3±16.4 µmol/l; p=0.487) and blood urea nitrogen (10.2±15.6 vs. 6.9±3.9 mmol/l; p=0.472) which were similar in both groups. The systolic anterior motion presence was significantly more frequent in patients caring MYH7 mutation (33% vs. 10%; p=0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p=0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p=0.001). The difference in diastolic function, i.e. E/e’ ratio between the two groups was also noted (MYBPC3 8.8±3.3, MYH7 13.9±6.9, p=0.079).Conclusions: Major findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.

Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy

“…A cross-sectional study design does not allow monitoring of disease progression. However, disease progression and response to pharmacological and lifestyle intervention in HCM is subject to our separate ongoing longitudinal SILICOFCM study [14,40].…”

The mechanics of the heart: zooming in on hypertrophic cardiomyopathy and cMyBP‐C

“…MYH7 variants have been traditionally associated with an earlier onset, more severe LVH and higher incidence of SCD and arrhythmias, while MYBPC3 variants have been linked to later onset, slower disease progression and better prognosis [57,232–234]. Indeed, this notion has been supported by recent studies and meta‐analyses retrieving data from literature [235–237]. Different age onset has also been reported depending on the underlying sarcomere gene variant [236].…”

Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN:c.40_42delAGA Carriers

“…To understand the incomplete penetrance and support early disease detection, researchers have been looking for environmental or genetic factors that modify the risk of disease manifestation. Typically, this research collects and analyzes phenotypical, environmental, and demographic information for carriers [8][9][10][11][12]. One very recent study by Verstraelen et al [13] used abnormalities observed in carriers to calculate the risk for malignant VA and guide the decision of when to start or withhold preventive therapies, including intracardiac defibrillators.…”