DO: 0110308;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q32.1 | Cardiomyopathy, hypertrophic, 2 | 115195 | Autosomal dominant | 3 | TNNT2 | 191045 |
A number sign (#) is used with this entry because of evidence that familial hypertrophic cardiomyopathy-2 (CMH2) is caused by heterozygous mutation in the cardiac troponin-T2 gene (TNNT2; 191045) on chromosome 1q32.
Watkins et al. (1993) reported a large family (family AU) of northern European descent segregating hypertrophic cardiomyopathy. On the basis of medical records, postmortem examination, or position in the pedigree, 11 deceased family members were considered to be affected. Fourteen of the 42 surviving first-degree relatives were affected, of whom 10 had symptoms (dyspnea in all 10, chest pain in 5, and syncope in 4). Electrocardiographic and 2-dimensional echocardiographic findings were abnormal in all 14 affected members. Maximum left ventricular wall thickness ranged from 1.3 to 3.0 cm; 2 affected individuals had undergone septal myectomy. A postmortem specimen from 1 individual, who died suddenly at age 15 years, demonstrated left ventricular hypertrophy and myocyte disarray.
By linkage studies in a large family (family AU) with familial hypertrophic cardiomyopathy not linked to the beta cardiac myosin heavy chain-beta gene (160760), Watkins et al. (1993) demonstrated that the disease locus was located on 1q3; the maximum multipoint lod score was 8.47. This locus was designated CMH2, CMH1 (192600) being the locus on chromosome 14 and CMH3 (115196) being the locus on chromosome 15. At least 1 other locus determining familial hypertrophic myopathy exists because some families are not linked to markers on any of these 3 chromosomes. Three sarcomeric contractile proteins--troponin I (191042), tropomyosin (191030), and actin (102610)--are located in a region on chromosome 1 making them strong candidate genes.
The transmission pattern of CMH2 in the families reported by Thierfelder et al. (1994) was consistent with autosomal dominant inheritance.
In 3 unrelated families with familial hypertrophic cardiomyopathy linked to chromosome 1q, including the family originally reported by Watkins et al. (1993), Thierfelder et al. (1994) identified heterozygous mutations in the TNNT2 gene (191045.0001-191045.0003).
Watkins et al. (1995) identified heterozygous mutations in the TNNT2 gene in affected members of 2 families with CMH (191045.0004 and 191045.0005).
In 6 of 46 unrelated Japanese CMH families, Anan et al. (1998) found the same phe110-to-ile mutation in the TNNT2 gene (F110I; 191045.0005) that had previously been identified by Watkins et al. (1995). Haplotype analysis supported a founder effect in 2 families, whereas the others had independent mutations; the authors suggested that F110I may represent a mutation hotspot. There was considerable inter- and intrafamilial phenotypic variability, with apical hypertrophy alone in 2 unrelated families. In contrast to other reported TNNT2 mutations, F110I appeared to show a favorable prognosis,
In a 3-generation family segregating autosomal dominant cardiomyopathy, in which the proband had a restrictive phenotype (RCM3; 612422) and relatives had clinical features of restrictive, hypertrophic, and/or dilated (CMD1D; 601494) cardiomyopathy, Menon et al. (2008) performed targeted linkage analysis for 9 sarcomeric genes and identified heterozygosity for the I79N mutation in the TNNT2 gene (191045.0001), previously reported by Thierfelder et al. (1994) in a family with hypertrophic cardiomyopathy. The mutation segregated with the disease phenotype and was not found in unaffected individuals. Despite the variable morphology, all affected members of the family exhibited restrictive physiology. There was a high incidence of atrial tachyarrhythmia but no significant ventricular arrhythmia or sudden death in affected members of this family.
Anan, R., Shono, H., Kisanuki, A., Arima, S., Nakao, S., Tanaka, H. Patients with familial hypertrophic cardiomyopathy caused by a phe110ile missense mutation in the cardiac troponin T gene have variable cardiac morphologies and a favorable prognosis. Circulation 98: 391-397, 1998. [PubMed: 9714088] [Full Text: https://doi.org/10.1161/01.cir.98.5.391]
Menon, S. C., Michels, V. V., Pellikka, P. A., Ballew, J. D., Karst, M. L., Herron, K. J., Nelson, S. M., Rodeheffer, R. J., Olson, T. M. Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology. Clin. Genet. 74: 445-454, 2008. [PubMed: 18651846] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01062.x]
Thierfelder, L., Watkins, H., MacRae, C., Lamas, R., McKenna, W., Vosberg, H.-P., Seidman, J. G., Seidman, C. E. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 77: 701-712, 1994. [PubMed: 8205619] [Full Text: https://doi.org/10.1016/0092-8674(94)90054-x]
Watkins, H., MacRae, C., Thierfelder, L., Chou, Y.-H., Frenneaux, M., McKenna, W., Seidman, J. G., Seidman, C. E. A disease locus for familial hypertrophic cardiomyopathy maps to chromosome 1q3. Nature Genet. 3: 333-337, 1993. [PubMed: 7981753] [Full Text: https://doi.org/10.1038/ng0493-333]
Watkins, H., McKenna, W. J., Thierfelder, L., Suk, H. J., Anan, R., O'Donoghue, A., Spirito, P., Matsumori, A., Moravec, C. S., Seidman, J. G., Seidman, C. E. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. New Eng. J. Med. 332: 1058-1064, 1995. [PubMed: 7898523] [Full Text: https://doi.org/10.1056/NEJM199504203321603]