Prevalence of cardiac beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is a frequent, autosomal-dominant cardiac disease and manifests predominantly as left ventricular hypertrophy. Mutations in the cardiac beta-myosin heavy chain gene (MYH7) are responsible for the disease in about 30% of cases where mutations were identified. We clinically evaluated a large group of 147 consecutive HCM patients from three cardiology centers in Germany, Poland, and Kyrgyzstan according to the same protocol. The DNA of the patients was systematically analyzed in the whole coding region of the MYH7 gene using PCR, single-strand conformation polymorphism analysis, and automated sequencing. Eleven different missense mutations (including seven novel ones) in 11 unrelated patients were identified, showing a mutation frequency of 7.5% in the study population. We further examined the families of five patients (three of German, one of Polish, and one of Kyrgyz origin) with 32 individuals in total. We observed a clear, age-dependent penetrance with onset of disease symptoms in the fourth decade of life. Genotype-phenotype correlations were different for each mutation, whereas the majority was associated with an intermediate/malign phenotype. In conclusion, we report a systematic molecular screening of the complete MYH7 gene in a large group of consecutive HCM patients, leading to a genetic diagnosis in 38 individuals. Information about the genotype in an individual from one family could be very useful for the clinician, especially when dealing with healthy relatives in doubt of their risk about developing HCM. The increasing application of genetic screening and the increasing knowledge about genotype-phenotype correlations will hopefully lead to an improved clinical management of HCM patients.

Cardiomyopathy Mutations in the Tail of β-Cardiac Myosin Modify the Coiled-coil Structure and Affect Integration into Thick Filaments in Muscle Sarcomeres in Adult Cardiomyocytes

“…This suggests that reducing the helical content could contribute to a decreased ability of these mutant isoforms to incorporate normally into thick filaments and an increased chance that the mutant myosin forms aggregates outside the muscle sarcomeres. This may explain why all three of these mutations result in a more severe form of HCM (supplemental Table S1) (18,20). The nonincorporated aggregated myosin may be proteotoxic, supporting the recently suggested idea that protein misfolding is a major contributor to hypertrophic cardiomyopathy (40).…”

“…To test this idea, we investigated five different mutations that result in HCM (15)(16)(17)(18)(19)(20)(21) and one (R1500W) that causes DCM (17). Only two of these mutations have been investigated previously (E1356K and R1500W (22,23)).…”

Unequal allelic expression of wild-type and mutated β-myosin in familial hypertrophic cardiomyopathy

“…Mutation V606M: Soleus biopsies were available from a British individual (H5; [45]) and from an unrelated American individual (H6; [12]. Mutation I736T: We obtained soleus biopsies from three siblings of a Kyrgyz family (Caucasian origin; [30]), one male (H18, Family A, II-2) and two females (H19, Family A, II-4 and H20, Family A, II-7) with moderate left ventricular and septal hypertrophy (14, 18, 17 mm, for H18, H19 and H20, respectively) and pathological ECGs. Mutation G584R: The biopsy was from a young British male [45].…”

Cardiomyopathy: A Systematic Review of Disease-Causing Mutations in Myosin Heavy Chain 7 and Their Phenotypic Manifestations

“…The symptoms displayed range from asymptomatic carrier status through to dizziness, palpitations, syncope and SCD. The age of onset also varies; some patients are diagnosed close to birth [5,6], while others remain asymptomatic until their third, fourth or even seventh decade [7,8,9]. There are 4 recognised classes of cardiomyopathy: hypertrophic, dilated, restrictive and arrhythmogenic right ventricular [4].…”