ORPHA: 154; DO: 0110434;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p21.1 | Cardiomyopathy, dilated, 1Z | 611879 | Autosomal dominant | 3 | TNNC1 | 191040 |
A number sign (#) is used with this entry because of evidence that dilated cardiomyopathy-1Z (CMD1Z) is caused by heterozygous mutation in the TNNC1 gene (191040), which encodes slow troponin-C, on chromosome 3p21.
Dilated cardiomyopathy-1Z (CMD1Z) is characterized by severe reduction in cardiac function, with onset in infancy or early childhood in some patients but diagnosis as late as the fifth decade in others. Patients exhibit biventricular systolic dysfunction, with severely reduced left ventricular ejection fractions. Most affected individuals require transplantation for survival (Mogensen et al., 2004; Kaski et al., 2007; Pinto et al., 2011).
For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see CMD1A (115200).
Mogensen et al. (2004) studied a 3-generation family (family A) with severe dilated cardiomyopathy in which the proband had sudden onset of heart failure at 21 years of age and underwent cardiac transplantation 2 months later. His mother died at 45 years of age awaiting cardiac transplantation, his maternal grandfather died of heart failure at 62 years of age after 8 months of medical treatment, and a maternal aunt had unexplained sudden death at 21 years of age. A maternal uncle and cousin received cardiac transplants at age 52 and 22 years, respectively; the uncle, who had normal cardiac function at the time of his son's transplant, developed heart failure 2 years later and required transplantation within 2 months of symptom onset. The proband also had a sister diagnosed with CMD at 17 years of age who was being treated with angiotensin-converting enzyme (ACE; 106180) inhibitors, and another sister who at age 36 years had left ventricular enlargement on echocardiography and ECG abnormalities. Histologic examination of specimens from an autopsy and an explanted heart showed nonspecific abnormalities including myocyte hypertrophy, increased interstitial fibrosis, and endocardial thickening with smooth muscle cells characteristic of CMD; there was no significant myocyte disarray characteristic of hypertrophic cardiomyopathy or features suggesting storage disease.
Kaski et al. (2007) reported a 3-year-old boy with severe dilated cardiomyopathy and mutation in the TNNC1 gene, who was the nephew of the proband in family A reported by Mogensen et al. (2004). The nephew presented with vomiting, lethargy, and dyspnea, and chest x-ray showed an enlarged heart and pulmonary edema. Echocardiography revealed biventricular dilation and poor biventricular systolic function, with a left ventricular ejection fraction of 20%. There was global left ventricular hypokinesis and severe mitral regurgitation. He experienced 2 respiratory arrests with bradycardia, and ultimately underwent successful orthotopic heart transplantation. Histologic analysis of the explanted heart showed nonspecific patchy fibrosis, particularly in the subendocardium. There was no evidence of myocytic disarray or hypertrophy. The authors noted that this was the first report of TNNC1-associated dilated cardiomyopathy presenting in childhood.
Pinto et al. (2011) provided clinical details for the family of proband D.2, originally reported by Hershberger et al. (2010) with CMD and mutation in the TNNC1 gene (see MOLECULAR GENETICS). Now designated as patient B.6 in pedigree B, the proband was a woman who was diagnosed with CMD at age 47 years and who also had atrial fibrillation with rapid ventricular response, premature ventricular contractions (PVCs), and a prolonged QT interval; she experienced cardiac arrest at age 49, after which she underwent placement of an implantable cardioverter-defibrillator (ICD) and a pacemaker. She had an affected sister (B.4) who was diagnosed with CMD at age 39 and had normal sinus rhythm and died of noncardiac causes at age 48. Both patients with CMD had evidence of myocardial infarction, which was anterolateral in proband B.6 and septal in patient B.4. There were 2 more sisters without CMD or mutation in the TNNC1 gene who had cardiac arrhythmias: patient B.3, who had palpitations and syncope, was screened at age 40 and had first-degree AV block and supraventricular tachycardia, and underwent placement of an ICD at age 41; patient B.5 was screened at age 47 and found to have sinus bradycardia, PVCs, and QT prolongation, and underwent placement of a pacemaker.
Johnston et al. (2019) reported an infant girl with dilated cardiomyopathy and mutation in the TNNC1 gene. She had difficulty feeding and severe failure to thrive from birth, and was diagnosed with CMD at age 6 weeks. Examination revealed severe hypotonia and global developmental delay. Echocardiography showed left ventricular hypertrabeculation and overt left ventricular and left atrial dilation. The proband died at 1 year of age after a viral infection with exacerbation of her cardiac dysfunction.
Udani et al. (2023) described 3 sibs with severe dilated pediatric cardiomyopathy. The 3-month-old proband was born to a 38-year-old mother with a history of uterine septum and transverse terminal upper limb defect and 12 prior miscarriages. There was no known family history of dilated cardiomyopathy. The proband came to attention after sudden death when she was found limp and cyanotic in her car seat. Prior to death, the infant had been healthy and active. Autopsy revealed endocardial fibroelastosis as well as renal lipidosis and hepatic steatosis. Prenatal echocardiogram had revealed moderate cardiomegaly with moderate to severe biventricular systolic dysfunction and moderate tricuspid regurgitation. Two subsequent pregnancies ended with fetal demise at 21 and 20 weeks' gestation and had similar echocardiographic findings.
The transmission pattern of CMD in the family reported by Mogensen et al. (2004) was consistent with autosomal dominant inheritance.
In 5 affected members of a 3-generation family (family A) with severe dilated cardiomyopathy, Mogensen et al. (2004) identified heterozygosity for a missense mutation in the TNNC1 gene (G159D; 191040.0001).
In a 3-year-old boy with severe CMD who underwent heart transplantation, who was the nephew of the proband in family A reported by Mogensen et al. (2004), Kaski et al. (2007) identified heterozygosity for the G159D mutation in the TNNC1 gene. Dyer et al. (2009) performed functional studies of mutant myocytes from the boy's explanted heart that showed an increased sensitivity to Ca(2+) with the mutant compared to wildtype TNNC1; however, dephosphorylation of troponin did not produce the expected increase in Ca(2+) sensitivity with the mutant cTnC. Dyer et al. (2009) suggested that uncoupling of the relationship between phosphorylation and Ca(2+) sensitivity might be the cause of the dilated cardiomyopathy phenotype in patients with G159D mutation.
In a cohort of 312 probands with dilated cardiomyopathy, Hershberger et al. (2010) analyzed 5 CMD-associated genes and identified a missense mutation in the TNNC1 gene (M103I; 191040.0008) in 1 proband (D.2). The mutation was also present in an affected relative, and was not found in 246 control individuals. Clinical details were not reported. Another 3 heterozygous TNNC1 missense variants were identified in 3 CMD probands, but segregation data was lacking for those variants, and 2 of the probands also had mutation in another CMD-associated gene. Pinto et al. (2011) restudied these families with TNNC1 variants, and reported that the M103I mutation, present in proband D.2 (now designated B.6) and her sister with CMD (B.4), was not found in their 2 other sisters (B.3 and B.5) who had severe cardiac arrhythmias but not CMD.
By trio whole-exome sequencing in an infant girl with CMD and her unaffected parents, Johnston et al. (2019) identified heterozygosity for a de novo missense mutation in the TNNIC1 gene (I4M; 191040.0009) that was not found in the gnomAD database. Functional analysis showed a reduction in the magnitude and rate of isometric force generation with the mutant, as well as tighter binding between cTnT (TNNT2; 191045) and cTnC.
Using duo whole-exome sequencing in a family in which 3 sibs had severe dilated pediatric cardiomyopathy, Udani et al. (2023) identified a de novo heterozygous missense mutation in the TNNC1 gene (G34R; 191040.0007) in the proband and first stillborn sib. Sanger sequencing identified the mutation in the second stillborn sib. Both parents and 2 unaffected sibs were negative for the mutation. The presence of the same de novo variant in all 3 affected sibs suggested germline mosaicism.
Dyer, E. C., Jacques, A. M., Hoskins, A. C., Ward, D. G., Gallon, C. E., Messer, A. E., Kaski, J. P., Burch, M., Kentish, J. C., Marston, S. B. Functional analysis of a unique troponin c mutation, GLY159ASP, that causes familial dilated cardiomyopathy, studied in explanted heart muscle. Circ. Heart Fail. 2: 456-464, 2009. [PubMed: 19808376] [Full Text: https://doi.org/10.1161/CIRCHEARTFAILURE.108.818237]
Hershberger, R. E., Norton, N., Morales, A., Li, D., Siegfried, J. D., Gonzalez-Quintana, J. Coding sequence rare variants identified in MYBPC3, MYH6, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. Circ. Cardiovasc. Genet. 3: 155-161, 2010. [PubMed: 20215591] [Full Text: https://doi.org/10.1161/CIRCGENETICS.109.912345]
Johnston, J. R., Landim-Vieira, M., Marques, M. A., de Oliveira, G. A. P., Gonzalez-Martinez, D., Moraes, A. H., He, H., Iqbal, A., Wilnai, Y., Birk, E., Zucker, N., Silva, J. L., Chase, P. B., Pinto, J. R. The intrinsically disordered C terminus of troponin T binds to troponin C to modulate myocardial force generation. J. Biol. Chem. 294: 20054-20069, 2019. [PubMed: 31748410] [Full Text: https://doi.org/10.1074/jbc.RA119.011177]
Kaski, J. P., Burch, M., Elliott, P. M. Mutations in the cardiac Troponin C gene are a cause of idiopathic dilated cardiomyopathy in childhood. Cardiol. Young 17: 675-677, 2007. [PubMed: 17977476] [Full Text: https://doi.org/10.1017/S1047951107001291]
Mogensen, J., Murphy, R. T., Shaw, T., Bahl, A., Redwood, C., Watkins, H., Burke, M., Elliott, P. M., McKenna, W. J. Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 44: 2033-2040, 2004. [PubMed: 15542288] [Full Text: https://doi.org/10.1016/j.jacc.2004.08.027]
Pinto, J. R., Siegfried, J. D., Parvatiyar, M. S., Li, D., Norton, N., Jones, M. A., Liang, J., Potter, J. D., Hershberger, R. E. Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy. J. Biol. Chem. 286: 34404-34412, 2011. [PubMed: 21832052] [Full Text: https://doi.org/10.1074/jbc.M111.267211]
Udani, R., Schilter, K. F., Tyler, R. C., Smith, B. A., Wendtandrae, J. L., Kappes, U. P., Scharer, G., Lehman, A., Steinraths, M., Reddi, H. V. A novel variant of TNNC1 associated with severe dilated cardiomyopathy causing infant mortality and stillbirth: a case of germline mosaicism. J. Genet. 102: 14, 2023. [PubMed: 36814108]