Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations.

EDITOR—Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease, which may aZict as many as 1 in 500 subjects. The disease is characterised by an unexplained local or general myocardial hypertrophy and by myocyte disarray. Molecular genetic studies have so far identified nine disease associated genes, all of which encode sarcomeric proteins. The two genes in which most mutations have been described are the â-myosin heavy chain (MYH7) and the myosin binding protein C (MYBPC3) genes, each of which may account for up to 30% of all familial cases. Mutations in á-tropomyosin (TPM1), troponin T (TNNT2), 6 troponin I (TNNI3), cardiac á-actin (ACTC), titin (TTN), and the essential (MYL3) and the regulatory (MYL2) myosin light chain genes have also been associated with FHC. This pronounced genetic heterogeneity may be the principal cause of the phenotypic variability that is seen in FHC. Thus, mutations in TNNT2 seem to be associated with sudden death at a young age, 11 whereas families with mutations in MYBPC3 are generally characterised by progressive hypertrophy and a late onset of clinical manifestation. 13 Furthermore, it has been proposed that a certain rare form of hypertrophic cardiomyopathy (HCM), asymmetric septal hypertrophy predominantly confined to the midventricular region, known as the midventricular hypertrophy (MVH) phenotype, may be associated with mutations in the two myosin light chain genes. However, limited and contradictory clinical information is available on FHC caused by mutations in these genes. 14 We have studied MYL2 and MYL3 in 68 consecutively collected FHC families from Denmark and in 130 probands from South Africa. We established the frequency of myosin light chain mutations and assessed whether mutations in these two genes do cause a distinct phenotype. Concurrently, we identified subjects with an MVH phenotype in the Danish families and investigated the segregation of this phenotype in their relatives. Subsequently, we screened the probands of these families, as well as those in which we identified mutations, irrespective of their clinical phenotype, for the presence of mutations in the coding regions of MYH7, MYBPC3, TNNT2, TPM1, TNNI3, and ACTC to assess the correlation between the MVH phenotype and the causal mutation.