BACKGROUND: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most frequent cardiomyopathies that cause acute heart failure and sudden cardiac death. Previous genetic reports have shown that pathogenic variants of genes encoding Z-disc components such as telethonin protein (TCAP) are the primary cause of DCM and HCM.
METHODS: This study was the first investigation on the TCAP gene among the Iranian cardiomyopathies population wherein the TCAP gene was analyzed in 40 unrelated patients (17 females and 23 males) who were clinically diagnosed with HCM and DCM. In addition, we conducted a thorough review of all published articles and the databases that were the first to report novel pathogenic or likely pathogenic variants the in TCAP gene.
RESULTS: In the cohort of this study, we identified only one intronic variant c.111-42G > A in one of the HCM patients that were predicted as polymorphism by in-silico analysis. Moreover, a total of 44 variants were reported for the TCAP gene in the literature where a majority of mutations were found to be missense. Pathogenic mutations in TCAP may cause diseases including limb-girdle muscular dystrophy 2G (LGMD-2G), DCM, HCM, intestinal pseudo-obstruction, and telethonin deficiency. However, a large number of affected patients were clinically diagnosed with limb-girdle 2G compared to other presenting phenotypes.
CONCLUSIONS: These findings suggest that the TCAP gene pathogenic mutations might not be a common cause of cardiomyopathies among Iranian patients. These gene disease-causing mutations may cause various manifestations, but it has a high prevalence among LGMD-2G, HCM, and DCM patients.

Mutations in TCAP gene cause autosomal recessive limb-girdle muscular dystrophy type 2G (LGMD2G), congenital muscular dystrophy and autosomal dominant dilated and hypertrophic cardiomyopathy. We studied 18 affected individuals from 12 pedigrees, belonging to a Bulgarian Muslim minority from the South-West of Bulgaria, homozygous for the c.75G>A, p.Trp25X mutation in TCAP gene. The heterozygous carrier rate of p.Trp25X among 100 newborns in this region was found to be 2%. The clinical features in the Bulgarian TCAP group include disease onset in the first to the third decade of life, proximal muscle weakness in the lower limbs, followed or accompanied by difficulties in ankle dorsiflexion and involvement of the proximal muscles of the upper limbs 5-9 years after the disease onset. Asymmetry between left and right was present in more than 20% of the affected. Respiratory and cardiac functions were not affected. On the MRI the muscles of the posterior pelvic area, thigh and anterior leg were predominantly affected, while sartorius, gracilis and biceps femoris muscles remained relatively spared. In conclusion, LGMD2G appears to be a common form among Bulgarian Muslims. Homozygosity for c.75G>A, p.Trp25X is associated with a homogeneous clinical presentation, but the clinical course and severity of the disease show inter- and intra-familial variation.

Limb girdle muscular dystrophy (LGMD) type 2G is a rare form of muscle disease, described only in a few patients worldwide, caused by mutations in TCAP gene, encoding the protein telethonin. It is characterised by proximal limb muscle weakness associated with distal involvement of lower limbs, starting in the first or second decade of life. We describe the case of a 37-year-old woman of Greek origin, affected by disto-proximal lower limb weakness. No cardiac or respiratory involvement was detected. Muscle biopsy showed myopathic changes with type I fibre hypotrophy, cytoplasmic vacuoles, lipid overload, multiple central nuclei and fibre splittings; ultrastructural examination showed metabolic abnormalities. Next generation sequencing analysis detected a homozygous frameshift mutation in the TCAP gene (c.90_91del), previously described in one Turkish family. Immunostaining and Western blot analysis showed complete absence of telethonin. Interestingly, Single Nucleotide Polymorphism analysis of the 10 Mb genomic region containing the TCAP gene showed a shared homozygous haplotype of both the Greek and the Turkish patients, thus suggesting a possible founder effect of TCAP gene c.90_91del mutation in this part of the Mediterranean area.