|(C;C)||0||common in clinvar|
A number of earlier studies have shown that mutations in TNNT2 can lead to dilated cardiomyopathy. [PMID 20031601] [PMID 20978592] [PMID 11779518] characterized by a thinning of the ventricular wall, or conversely, hypertrophic cardiomyopathy (HCM), characterized by a thickening of the ventricular wall. Both conditions lead to an overall weakening of the heart muscle and can lead to heart failure or sudden cardiac death. [PMID 11239412] The molecular mechanisms whereby mutations in the same gene (TNNT2) can lead to two diseases (DCM and HCM) with such contrasting phenotypes are still not well-understood.
In a study by Li et al, rs3729547 (C to T) and another tagging SNP also in TNNT2, rs3729843 (G to A), were shown to be associated with DCM in a cohort of Han Chinese individuals (X2= 6.63, P = 0.036; X2 = 9.787, P = 0.008, respectively) The risk allele for rs3729547 is T and the risk allele for rs3729843 is A. rs3729547 is a synonymous (isoleucine) variant whereas rs3729843 is a noncoding SNP. In this study, the authors investigated the association between 10 tagging SNPs (these two included) and DCM using matrix-assisted laser desorption/ionization, time-of-flight mass spectrometry (MALDI-TOF-MS). However, the patients from this study were all members of the Han Chinese population, and therefore, these SNPs must be studied in the context of another ethnic group to validate strong associations between these SNPs and DCM. Additionally, this study was limited by its sample size, as only 97 DCM patients and 189 healthy unrelated controls partook in this study. [PMID 23586019]
In a second study published by Rani et al, the TNNT2 gene was sequenced in 162 patients with hypertrophic cardiomyopathy (HCM) and in 179 healthy controls. HCM phenotype ranged from moderate to severe, but a limited number of corrective operations were performed in these HCM patients. In contrast to the Li et al paper, this study was conducted exclusively in patients from India. Fifteen associated variants were uncovered, including rs3729547 (C to T) and rs3729843 (G to A), which were found to be in high linkage disequilibrium in the HCM patients. They also identified a 5bp deletion polymorphism in this Indian population that was previously shown to be associated with HCM patients of French, Spanish, and Japanese origin. [PMID 20978592][PMID 23586019] Tnnt2 gene polymorphisms are associated with susceptibility to idiopathic dilated cardiomyopathy in the han chinese population.
[PMID 22017532] Cardiac troponin t (tnnt2) mutations are less prevalent in indian hypertrophic cardiomyopathy patients.
[PMID 11239412] The genetic basis for cardiomyopathy: From mutation identification to mechanistic paradigms.
[PMID 20031601] Clinical and functional characterization of tnnt2 mutations identified in patients with dilated cardiomyopathy
[PMID 20978592] Recurrent and founder mutations in the netherlands: Mutation p.K217del in troponin t2, causing dilated cardiomyopathy.
[PMID 11779518] A novel mutation lys273glu in the cardiac troponin t gene shows high degree of penetrance and transition from hypertrophic to dilated cardiomyopathy.
[PMID 20592870] Comparison of the Illumina Genome Analyzer and Roche 454 GS FLX for resequencing of hypertrophic cardiomyopathy-associated genes.
[PMID 26400351] Significance of sarcomere gene mutation in patients with dilated cardiomyopathy