First description of germline mosaicism in familial hypertrophic cardiomyopathy

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 aVected 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 aVected 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 aVect her somatic cells. Such a phenomenon might account for some de novo mutations in familial hypertrophic cardiomyopathy. (J Med Genet 2000;37:132-134) Keywords: hypertrophic cardiomyopathy; germline mosaicism; myosin heavy chain; genetics Familial hypertrophic cardiomyopathy (FHC) is characterised by hypertrophy of the nondilated left ventricle with predominant involvement of the interventricular septum (IVS) in the absence of other causes of hypertrophy.1 It is a genetically and phenotypically heterogeneous disease transmitted as an autosomal dominant trait. There is considerable clinical heterogeneity and most patients are asymptomatic or have mild symptoms such as dyspnoea, chest pain, or lipothymia.2 The major complications are sudden cardiac death 3 and severe heart failure. Clinical diagnosis of FHC is routinely based on ECG and echocardiographic abnormalities as described in children 4 and adults. 5 The genetic heterogeneity of this disease is illustrated by the identification of mutations in seven genes coding for sarcomeric proteins. Three contractile proteins are encoded by the myosin heavy chain gene (MYH7) located on chromosome 14, the ventricular myosin essential light chain 1 gene (MYL3) on chromosome 3, and the ventricular myosin regulatory light chain 2 gene (MYL2) on chromosome 12. Three associated proteins are encoded by the cardiac troponin T gene (TNNT2) on chromosome 1, the cardiac troponin I gene (TNNI3) on chromosome 19, and the tropomyosin gene (TPM1) on chromosome 15. The last protein is the cardiac myosin binding protein C encoded by the MYBPC3 gene on chromosome 11.6 All these proteins are involved in sarcomeric function and hypertrophy is considered t...

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