TNNT2 – Dilated Cardiomyopathy

Cardiac troponin T (TNNT2) is a component of the thin‐filament troponin complex critical for calcium‐mediated regulation of cardiac muscle contraction. Heterozygous TNNT2 variants perturb tropomyosin binding and sarcomere function, leading to autosomal dominant dilated cardiomyopathy (DCM) characterised by ventricular dilation and systolic dysfunction.

Autosomal dominant inheritance is supported by multiple multiplex families. Bidirectional resequencing of 313 DCM probands identified 6 protein‐altering TNNT2 variants in 9 probands (PMID:20031601). Exome sequencing in a large pedigree revealed c.547C>T (p.Arg183Trp) segregating with DCM in 4 distant relatives across two families (PMID:24205113). A recurrent founder deletion p.Lys220del (c.650AGA[3]) was detected in 6 patients from 4 Dutch families (PMID:20978592). In a Swedish kindred, c.548G>A (p.Arg183Gln) was found in 4 affected individuals presenting in infancy or childhood (PMID:28669108). Altogether >25 probands and ≥19 affected relatives have been reported.

The TNNT2 variant spectrum comprises predominantly missense changes clustering in the tropomyosin‐binding TNT1 region (residues 80–180). Hotspots include codons Arg141, Arg149, Arg183, and Arg215. The c.643C>T (p.Arg215Trp) allele is illustrative of a recurring DCM‐causing variant.

Functional assays across multiple model systems demonstrate concordant pathogenic effects. In vitro reconstituted thin filaments bearing DCM mutants exhibit reduced Ca2+ sensitivity in ATPase and motility assays (PMID:15923195). Skinned cardiac muscle fibers with mutant troponin T show decreased force generation at physiological pH (PMID:20031601). Gene‐targeted mice heterozygous for the R141W mutation develop ventricular dilation, reduced contractility, and Ca2+ desensitization (PMID:27936050). Human iPSC‐derived cardiomyocytes with DCM‐associated TNNT2 variants display decreased microtissue contraction consistent with sarcomere dysfunction (PMID:33025817).

These data support a dominant‐negative and haploinsufficiency mechanism whereby TNNT2 variants impair troponin–tropomyosin interactions, depress myofilament Ca2+ responsiveness, and lead to progressive DCM. Extensive segregation, recurrence, and multi‐species functional concordance warrant a Definitive ClinGen association.

Genetic testing for TNNT2 variants should be considered in individuals with DCM, as identification of pathogenic alleles informs family screening, prognosis, and management. Key take‐home: TNNT2 is a definitive DCM gene, with >30 pathogenic missense alleles causing sarcomere Ca2+ desensitization and autosomal dominant cardiomyopathy.

References

• Clinical and functional characterization of TNNT2 mutations identified in patients with dilated cardiomyopathy. Circulation: Cardiovascular Genetics | 2009 PMID:20031601
• Recurrent and founder mutations in the Netherlands: mutation p.K217del in troponin T2, causing dilated cardiomyopathy. Netherlands Heart Journal | 2010 PMID:20978592
• Exome sequencing identifies a troponin T mutation hot spot in familial dilated cardiomyopathy. PLoS One | 2013 PMID:24205113
• Novel Genetic Variants in BAG3 and TNNT2 in a Swedish Family with a History of Dilated Cardiomyopathy and Sudden Cardiac Death. Pediatric Cardiology | 2017 PMID:28669108
• Gene‐targeted mice with the human troponin T R141W mutation develop dilated cardiomyopathy with calcium desensitization. PLoS One | 2016 PMID:27936050
• Development of a cardiac sarcomere functional genomics platform to enable scalable interrogation of human TNNT2 variants. Circulation | 2020 PMID:33025817
• Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype. J Biol Chem | 2005 PMID:15923195

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