Alternative titles; symbols
DO: 0110314;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p21.31 | Cardiomyopathy, hypertrophic, 8 | 608751 | Autosomal dominant; Autosomal recessive | 3 | MYL3 | 160790 |
A number sign (#) is used with this entry because of evidence that familial hypertrophic cardiomyopathy-8 (CMH8) is caused by heterozygous or homozygous mutation in the MYL3 gene (160790) on chromosome 3p21.
For a general phenotypic description and a discussion of genetic heterogeneity of hypertrophic cardiomyopathy, see CMH1 (192600).
Poetter et al. (1996) studied a large 3-generation family segregating autosomal dominant hypertrophic cardiomyopathy (CMH), in which 6 of 13 affected individuals had a rare variant of cardiac hypertrophy that involved mid-left ventricular chamber thickening apparent in the left ventriculogram and was associated with a pressure gradient detectable by Doppler echocardiography. Massive hypertrophy of the cardiac papillary muscles and adjacent ventricular tissue was present, causing a midcavitary obstruction. Soleus or deltoid muscle biopsies from 3 patients showed myopathic changes and a ragged-red fiber pattern characteristic of primary mitochondrial disease; cytochrome oxidase-positive subsarcolemmal accumulations were confirmed to be mitochondria by electron microscopy. Poetter et al. (1996) also ascertained a young boy with massive mid-left ventricular chamber obstruction, and stated that it was even more rare to find this phenotype in a child.
Autosomal recessive inheritance of CMH8 was suspected in a 5-generation consanguineous family reported by Olson et al. (2002). Three male sibs, the products of a second-cousin marriage, developed a cardiomyopathy in the second decade of life. Two died within 2 years of diagnosis. The surviving affected child, the proband, had left ventricular hypertrophy and repolarization abnormalities on his ECG. His echocardiogram demonstrated midcavitary left ventricular hypertrophy with mild obstruction during systole. Restrictive physiology was suggested by mild pulmonary hypertension and severe biatrial enlargement. Similar investigations in the child's parents, paternal grandparents, and asymptomatic sister were all normal.
Poetter et al. (1996) analyzed the MYL3 gene (160790) in 383 unrelated probands with hypertrophic cardiomyopathy and identified a heterozygous missense mutation at a conserved residue (M149V; 160790.0001) that segregated with disease in a large 3-generation family. Linkage analysis of the mutation against hypertrophy gave a lod score of 6.2 with no recombinants. Six of 13 affected family members had unusual mid-left ventricular chamber thickening on echocardiography, thus Poetter et al. (1996) screened an additional 16 unrelated CMH patients with similar mid-left ventricular chamber thickening for mutations in MYL3 and identified a different heterozygous missense mutation (R154H; 160790.0002) in a young boy with massive chamber obstruction. Neither these mutations nor any other mutations in MYL3 were identified in 378 control chromosomes or 762 chromosomes from unrelated CMH kindreds.
In a consanguineous family in which 3 sibs had early-onset hypertrophic cardiomyopathy characterized by midcavitary hypertrophy and restrictive physiology, Olson et al. (2002) performed haplotype analysis using polymorphic DNA markers spanning genes known to cause hypertrophic cardiomyopathy. The results suggested that, in keeping with the consanguineous family history, the phenotype might be an autosomal recessive form of CMH caused by mutation in MYL3. Homozygosity for a glu143-to-lys (E143K; 160790.0003) substitution in MYL3 was subsequently identified in the proband. The authors suggested that, in contrast to autosomal dominant CMH mutations in which functional studies demonstrate a dominant-negative effect, E143K was likely to cause loss of function. In support of this hypothesis, the authors found that heterozygotes were unaffected on the basis of electrocardiography and echocardiography. Olson et al. (2002) concluded that this family demonstrated a true autosomal recessive form of CMH8, characterized by a unique pattern of hypertrophy previously described in autosomal dominant CMH8.
In the proband from a CMH family previously described by Maron et al. (1982), in which 6 of 12 affected members had prototypic asymmetric hypertrophy and 6 had ventricular septal hypertrophy that was localized to the apical region of the left ventricle, Arad et al. (2005) identified heterozygosity for the same M149V mutation that had previously been found in patients with mid-left ventricular chamber hypertrophy (Poetter et al., 1996). Arad et al. (2005) noted that because the classification of hypertrophy as midcavitary or apical might in part reflect the evolution of diagnostic imaging techniques from angiography, by which midcavitary hypertrophy was historically recognized, to echocardiography and MRI, these may represent overlapping morphologies.
Arad, M., Penas-Lado, M., Monserrat, L., Maron, B. J., Sherrid, M., Ho, C. Y., Barr, S., Karim, A., Olson, T. M., Kamisago, M., Seidman, J. G., Seidman, C. E. Gene mutations in apical hypertrophic cardiomyopathy. Circulation 112: 2805-2811, 2005. [PubMed: 16267253] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.105.547448]
Maron, B. J., Bonow, R. O., Seshagiri, T. N. R., Roberts, W. C., Epstein, S. E. Hypertrophic cardiomyopathy with ventricular septal hypertrophy localized to the apical region of the left ventricle (apical hypertrophic cardiomyopathy). Am. J. Cardiol. 49: 1838-1848, 1982. [PubMed: 6211078] [Full Text: https://doi.org/10.1016/0002-9149(82)90200-4]
Olson, T. M., Karst, M. L., Whitby, F. G., Driscoll, D. J. Myosin light chain mutation causes autosomal recessive cardiomyopathy with mid-cavitary hypertrophy and restrictive physiology. Circulation 105: 2337-2340, 2002. [PubMed: 12021217] [Full Text: https://doi.org/10.1161/01.cir.0000018444.47798.94]
Poetter, K., Jiang, H., Hassanzadeh, S., Master, S. R., Chang, A., Dalakas, M. C., Rayment, I., Sellers, J. R., Fananapazir, L., Epstein, N. D. Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nature Genet. 13: 63-69, 1996. [PubMed: 8673105] [Full Text: https://doi.org/10.1038/ng0596-63]