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First description of germline mosaicism in familial hypertrophic cardiomyopathy
J F Forissier1, P Richard, S Briault
1Service de Cardiologie, Hôpital Trousseau, 37044 Tours Cedex, France.
Insights
Germline mosaicism, a rare phenomenon where a mutation appears in reproductive cells but not the body, is identified in hypertrophic cardiomyopathy. This finding may explain some familial hypertrophic cardiomyopathy cases previously thought to be de novo mutations.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Familial hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic disorder.
- It is typically inherited in an autosomal dominant pattern, but de novo mutations can occur.
- Mutations in sarcomeric protein genes are the primary cause of HCM.
Purpose of the Study:
- To investigate the genetic basis of hypertrophic cardiomyopathy in a French family with two affected members.
- To identify the underlying genetic mutation and understand its inheritance pattern.
- To explore the potential role of germline mosaicism in familial HCM.
Main Methods:
- Clinical screening using electrocardiography and echocardiography.
- Genetic analysis of leukocyte DNA, including haplotype analysis at the MYH7 locus.
- Mutation screening using single-strand conformation polymorphism (SSCP) analysis.
Main Results:
- Two family members presented with severe hypertrophic cardiomyopathy.
- A mutation (Arg453Cys) was identified in exon 14 of the MYH7 gene in affected individuals.
- The mutation was absent in the parents' somatic cells (leukocytes, fibroblasts, hair) but present in the mother's germline, indicating germline mosaicism.
Conclusions:
- This study provides the first molecular genetic evidence of germline mosaicism in an autosomal dominant disorder, specifically hypertrophic cardiomyopathy.
- The identified MYH7 mutation was inherited from the mother via germline mosaicism, not affecting her somatic cells.
- Germline mosaicism may account for a subset of familial hypertrophic cardiomyopathy cases previously attributed to de novo mutations.
Abstract:
Familial hypertrophic cardiomyopathy is a genetically and phenotypically heterogeneous disease caused by mutations in seven sarcomeric protein genes. It is known to be transmitted as an autosomal dominant trait with rare de novo mutations.A French family in which two members are affected by hypertrophic cardiomyopathy was clinically screened with electrocardiography and echocardiography. Genetic analyses were performed on leucocyte DNA by haplotype analysis with microsatellite markers at the MYH7 locus and mutation screening by single strand conformation polymorphism analysis. Two subjects exhibited severe hypertrophic cardiomyopathy. A mutation in the MYH7 gene was found in exon 14 (Arg453Cys). The two affected patients were carriers of the mutation, which was not found in the circulating lymphocytes of their parents. Haplotype analysis at the MYH7 locus with two intragenic microsatellite markers (MYOI and MYOII) and the absence of the mutation in the father's sperm DNA suggested that the mutation had been inherited from the mother. However, it was not found in either her fibroblasts or hair. This is the first description of germline mosaicism shown by molecular genetic analysis in an autosomal dominant disorder and more especially in hypertrophic cardiomyopathy. This mosaicism had been inherited from the mother but did not affect her somatic cells. Such a phenomenon might account for some de novo mutations in familial hypertrophic cardiomyopathy.