TCAP – Telethonin-related Hypertrophic Cardiomyopathy

Telethonin (TCAP) has been implicated in autosomal dominant hypertrophic cardiomyopathy ([MONDO:0005045]). In 389 unrelated HCM patients, 4 (4.1%) carried heterozygous TCAP variants—including c.208C>T (p.Arg70Trp), c.269C>T (p.Pro90Leu), c.493C>G (p.Gln165Glu), and c.34GAG[1] (p.Glu13del)—(PMID:16352453). A Danish cohort of 90 index cases identified two additional missense variants, c.34GAG[1] (p.Glu13del) and c.316C>T (p.Arg106Cys), in probands with familial HCM (PMID:19035361). Functional yeast two-hybrid and GST pull-down assays show that HCM-associated mutations such as c.410C>T (p.Thr137Ile) augment TCAP interaction with titin and calsarcin-1, consistent with a gain-of-function pathogenic mechanism (PMID:15582318).

Genetic evidence is limited by six unrelated probands and absence of segregation data. Functional experiments provide moderate support for a mechanistic link between TCAP variants and sarcomeric dysregulation. No large pedigrees or case–control studies have established penetrance or variant frequency. Overall, the clinical validity of TCAP in HCM is Limited. Key Take-home: While rare TCAP variants can contribute to HCM pathogenesis, their low prevalence and lack of segregation data warrant cautious interpretation in clinical testing.

References

• Molecular genetics and metabolism • 2006 • Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin. PMID:16352453
• Human mutation • 2009 • Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives. PMID:19035361
• Journal of the American College of Cardiology • 2004 • Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. PMID:15582318

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