TCAP – Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and systolic dysfunction. Rare missense variants in TCAP, encoding the Z-disc protein telethonin, have been implicated in DCM pathogenesis. A single DCM proband carrying c.394G>C (p.Glu132Gln) demonstrated impaired telethonin interactions with muscle LIM protein, titin, and calsarcin-1, supporting a pathogenic role in sarcomere stretch sensing (PMID:15582318). While segregation data are lacking, functional assays provide moderate mechanistic evidence of altered Z-disc binding.

Further support arises from sarcomeric interactome mapping: nesprin-2 isoforms bind telethonin in cardiomyocytes, and disease-associated TCAP mutations impair these interactions, suggesting disruption of sarcomeric organization in DCM (PMID:38569934). No large pedigrees or recurrent founder variants have been described for TCAP-related DCM, and case–control studies of common TCAP polymorphisms did not identify strong associations in sporadic cohorts.

Overall, the clinical validity of TCAP in DCM remains Limited given the small number of probands and absence of segregation, balanced by Moderate functional evidence. TCAP variant screening may be considered in comprehensive cardiomyopathy panels, but diagnostic weight should be cautious and supported by functional follow-up.

Key Take-home: Rare TCAP missense variants can disrupt Z-disc interactions and may contribute to DCM, yet current evidence warrants reservation in clinical interpretation.

References

• Journal of the American College of Cardiology • 2004 • Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. PMID:15582318
• The Journal of biological chemistry • 2024 • Nesprin-2 is a novel scaffold protein for telethonin and FHL-2 in the cardiomyocyte sarcomere. PMID:38569934

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