ORPHA: 154; DO: 0110430;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q31.2 | Cardiomyopathy, dilated, 1G | 604145 | Autosomal dominant | 3 | TTN | 188840 |
A number sign (#) is used with this entry because of evidence that autosomal dominant dilated cardiomyopathy-1G (CMD1G) is caused by heterozygous mutation in the titin gene (TTN; 188840) on chromosome 2q31.
Dilated cardiomyopathy-1G (CMD1G) is an autosomal dominant disorder characterized by ventricular dilatation and systolic contractile dysfunction (Siu et al., 1999).
For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy (CMD), see CMD1A (115200).
Siu et al. (1999) described a large Native American kindred (family MAO) with dilated cardiomyopathy and mutation in the TTN gene (Gerull et al., 2002). None of the 12 affected family members over 3 generations experienced antecedent conduction system disease and none had skeletal muscle dysfunction. Some patients in the family had early-onset CMD with a rapidly progressive course, including 2 children, aged 9 and 13 years, who had significant ventricular chamber dilation, and 2 young women, aged 16 and 21 years, who required treatment for congestive heart failure. However, 2 adult fathers with affected children showed neither signs nor symptoms of cardiomyopathy, although 1 of them died suddenly at age 50 from circulatory collapse with Rocky Mountain spotted fever. Premature death due to congestive heart failure occurred in 5 patients, and 2 underwent cardiac transplantation for end-stage heart failure. Explanted hearts and postmortem examinations showed moderate-to-massive cardiac enlargement without evidence of significant coronary artery disease. Histologic studies revealed myocyte hypertrophy without myofibrillar disarray, and diffuse interstitial fibrosis without inflammation.
Herman et al. (2012) reported 54 patients with dilated cardiomyopathy and mutation in the TTN gene. Premature deaths, in the third to sixth decade of life, were tabulated. Cardiac arrhythmias were observed in most patients, including atrial fibrillation and nonsustained ventricular tachycardia, and cardiac conduction defects included first-degree atrioventricular block, right and left bundle branch blocks, and left anterior fascicular block.
The transmission pattern of CMD1G in the families reported by Gerull et al. (2002) was consistent with autosomal dominant inheritance with incomplete penetrance.
In a Native American kindred (family MAO) with autosomal dominant transmission of dilated cardiomyopathy, in which disease was nonpenetrant in 2 obligate carriers, Siu et al. (1999) performed linkage analysis and identified a novel disease locus at marker D2S1244 on 2q31 (maximum lod = 4.06 at theta = 0.0) between the glucagon gene (138030) and marker D2S72; they designated this locus CMD1G. Because the massive gene encoding titin, a cytoskeletal muscle protein, resides in this disease interval, the authors analyzed sequences encoding 900-amino acid residues of the cardiac-specific (N2-B) domain of the gene. Although 5 sequence variants were identified, none segregated with the disease in this family.
By linkage and haplotype analysis in a large 4-generation family with dilated cardiomyopathy (kindred A1), Gerull et al. (2002) confirmed the CMD1G locus and refined the gene interval to 7.7 cM, between D2S326 and D2S2310, obtaining a maximum lod score of 5 at a penetrance of 0.70.
In 2 unrelated families with autosomal dominant dilated cardiomyopathy, Gerull et al. (2002) identified 2 different heterozygous mutations in the TTN gene: in kindred A1, the mutation was a 2-bp insertion (188840.0002); and in kindred MAO, originally studied by Siu et al. (1999), the mutation was a missense substitution (W930R; 188840.0003). Both families showed reduced penetrance and no involvement of noncardiac muscle. The latter was surprising since exons of TTN that contain the 2 CMD-causing mutations are both expressed in cardiac and noncardiac muscle isoforms.
In 4 patients with dilated cardiomyopathy, Itoh-Satoh et al. (2002) identified 4 different mutations in the TTN gene (188840.0007-188840.0010). Two of the cases were familial.
Herman et al. (2012) used next-generation sequencing to analyze the TTN gene in 203 individuals with dilated cardiomyopathy, 231 with hypertrophic cardiomyopathy (CMH), and 249 controls. The frequency of TTN mutations was significantly higher among individuals with CMD (27%) than among those with CMH (1%) or controls (3%). In CMD families, TTN mutations cosegregated with dilated cardiomyopathy, with highly observed penetrance (greater than 95%) after the age of 40 years. Mutations associated with CMD were overrepresented in the titin A-band but were absent from the Z-disc and M-band regions of titin. Overall, rates of cardiac outcomes were similar in individuals with or without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers. Herman et al. (2012) concluded that TTN truncating mutations are the most common known genetic cause of dilated cardiomyopathy, occurring in approximately 25% of familial CMD cases and in 18% of sporadic cases.
In assays of contractile function using cardiac microtissues (CMTs) engineered from human induced pluripotent stem (iPS) cells, Hinson et al. (2015) found that, like TTN-truncating variants (TTNtvs), certain missense mutations (e.g., W976R, 188840.0003) diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, Hinson et al. (2015) explained why truncations in the A-band domain of TTN cause dilated cardiomyopathy, whereas truncations in the I-band are better tolerated. Finally, the authors demonstrated that mutant titin protein in iPS cell-derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and beta-adrenergic stress, and attenuated growth factor and cell signaling activation. Hinson et al. (2015) concluded that titin mutations cause dilated cardiomyopathy by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.
Gerull, B., Gramlich, M., Atherton, J., McNabb, M., Trombitas, K., Sasse-Klaassen, S., Seidman, J. G., Seidman, C., Granzier, H., Labeit, S., Frenneaux, M., Thierfelder, L. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nature Genet. 30: 201-204, 2002. [PubMed: 11788824] [Full Text: https://doi.org/10.1038/ng815]
Herman, D. S., Lam, L., Taylor, M. R. G., Wang, L., Teekakirikul, P., Christodoulou, D., Conner, L., DePalma, S. R., McDonough, B., Sparks, E., Teodorescu, D. L., Cirino, A. L., and 17 others. Truncations of titin causing dilated cardiomyopathy. New Eng. J. Med. 366: 619-628, 2012. [PubMed: 22335739] [Full Text: https://doi.org/10.1056/NEJMoa1110186]
Hinson, J. T., Chopra, A., Nafissi, N., Polacheck, W. J., Benson, C. C., Swist, S., Gorham, J., Yang, L., Schafer, S., Sheng, C. C., Haghighi, A., Homsy, J., Hubner, N., Church, G., Cook, S. A., Linke, W. A., Chen, C. S., Seidman, J. G., Seidman, C. E. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science 349: 982-986, 2015. [PubMed: 26315439] [Full Text: https://doi.org/10.1126/science.aaa5458]
Itoh-Satoh, M., Hayashi, T., Nishi, H., Koga, Y., Arimura, T., Koyanagi, T., Takahashi, M., Hohda, S., Ueda, K., Nouchi, T., Hiroe, M., Marumo, F., Imaizumi, T., Yasunami, M., Kimura, A. Titin mutations as the molecular basis for dilated cardiomyopathy. Biochem. Biophys. Res. Commun. 291: 385-393, 2002. [PubMed: 11846417] [Full Text: https://doi.org/10.1006/bbrc.2002.6448]
Siu, B. L., Niimura, H., Osborne, J. A., Fatkin, D., MacRae, C., Solomon, S., Benson, D. W., Seidman, J. G., Seidman, C. E. Familial dilated cardiomyopathy locus maps to chromosome 2q31. Circulation 99: 1022-1026, 1999. [PubMed: 10051295] [Full Text: https://doi.org/10.1161/01.cir.99.8.1022]