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Beta-myosin heavy chain gene mutations and hypertrophic cardiomyopathy in Austrian children
S Greber-Platzer1, M Marx, C Fleischmann
1Department of Pediatrics, Division of Pediatric Cardiology, University of Vienna, Währinger Gürtel 18-20, Vienna, A-1090, Austria. Susanne.Greber-Platzer@akh-wien.ac.at
Insights
Genetic screening identified novel missense mutations in the beta-myosin heavy chain gene causing hypertrophic cardiomyopathy. Familial cases showed milder symptoms, while sporadic cases presented with severe left ventricular hypertrophy and clinical issues.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Hypertrophic cardiomyopathy (HCM) presents as familial or sporadic forms.
- Genetic mutations in sarcomeric proteins are key causes of HCM.
- Missense mutations in the cardiac beta-myosin heavy chain gene are implicated in familial HCM.
Purpose of the Study:
- To screen the beta-myosin heavy chain gene in children from Austrian families with HCM (group A) and sporadic HCM (group B).
- To identify novel and known missense mutations associated with different HCM phenotypes.
- To correlate genetic findings with clinical manifestations in affected children and adults.
Main Methods:
- Genetic screening of the beta-myosin heavy chain gene.
- Analysis of mutations in nine Austrian familial HCM families (group A) and seven sporadic HCM cases (group B).
- Clinical assessment of affected individuals to evaluate symptom severity and phenotype.
Main Results:
- Identified two known (V606M, R453C) and two novel (V406M, R663H) missense mutations in group A.
- Detected one known (R249Q) and one novel (M877K) missense mutation in group B.
- Group A children had mild/no symptoms; group B children showed significant left ventricular hypertrophy and symptoms like chest pain and dyspnea.
- Adults in group A exhibited varied clinical symptoms.
Conclusions:
- The V406M mutation may be associated with a more severe, potentially life-threatening form of HCM, possibly linked to sudden death.
- The R663H mutation appears to be more benign, leading to late-onset HCM with milder symptoms.
- Genetic mutations in the beta-myosin heavy chain gene significantly influence the clinical presentation and severity of hypertrophic cardiomyopathy.
Abstract:
Hypertrophic cardiomyopathy occurs in two variants, either as an autosomal dominant familial disorder or as a sporadic disease without familial involvement. Different genes coding sarcomeric proteins of the heart have been identified as causing hypertrophic cardiomyopathy. Missense mutations in the cardiac beta-myosin heavy chain gene are found in 30% of all cases of familial hypertrophic cardiomyopathy. We screened the beta-myosin heavy chain gene of children of nine Austrian families with hypertrophic cardiomyopathy (referred to as group A) and of seven children with sporadic hypertrophic cardiomyopathy (referred to as group B). We were able to find two previously described (V606M, R453C) and two unknown missense mutations (V406M, R663H) in group A. Additionally, in two children of group B we could identify one already known missense mutation, R249Q as well as one previously unknown missense mutation, M877K. The genetically affected children of group A developed no or only mild clinical symptoms, whereas the children of group B with genetically confirmed sporadic hypertrophic cardiomyopathy showed manifest left ventricular hypertrophy and clinical symptoms including chest pain and dyspnoea. Clinical symptoms among the adults of group A, suffering from familial hypertrophic cardiomyopathy, varied significantly. We therefore believe V406M to be a more malignant missense mutation, probably linked with sudden death in the affected family, than R663H, which seems to be more benign causing late-onset hypertrophic cardiomyopathy and mild clinical symptoms in the affected family members.