Telethoninopathy via the TCAP Gene

Variants in the titin-CAP (TCAP) gene, which encodes the sarcomeric protein telethonin, cause limb girdle muscular dystrophy type 2G (LGMD2G; OMIM 601954; Moreira et al. Nat Genet 24:163-166, 2000), dilated cardiomyopathy type 1N (CMD1N; OMIM 607487; Knöll et al. Cell 111:943-955, 2002), and hypertrophic cardiomyopathy (Hayashi et al. J Am Coll Cardiol 44:2192-2201, 2004). Affected members from three families with the LGMD phenotype have been reported to have disease onset between 2 and 15 years of age with variability in clinical severity. Marked weakness in the distal muscles of the legs manifests itself as difficulty with walking, running, and climbing stairs (Moreira et al. Am J Hum Genet 61:151-159, 1997). Some, but not all, reported patients lost the ability to walk in the 2nd to 4th decade of life (Moreira et al. 2000). Serum CK levels were slightly elevated in clinically mild cases, while those with earlier onset and more severe muscle weakness had 10- to 30-fold increased serum CK levels, calf hypertrophy, and dystrophic muscle biopsies (Moreira et al. 2000). Heart involvement was reported in three of six affected members of one family (Moreira et al. 2000). Foot drop and absent tendon reflexes without involvement of sensory and cranial nerves were found to be a common feature (Moreira et al. 1997). Heterozygous TCAP variants have also been documented to be one cause of dilated (DCM) and hypertrophic (HCM) cardiomyopathy.

Limb girdle muscular dystrophy due to TCAP variants is inherited as an autosomal recessive condition. Telethonin-associated cardiomyopathy occurs sporadically or is inherited as an autosomal dominant condition. The TCAP gene (OMIM 604488) encodes telethonin, a sarcomeric protein localized to the Z disc and a substrate for the protein titin. Limb girdle muscular dystrophy and cardiomyopathy are genetically heterogeneous; therefore, a negative TCAP sequencing test does not rule out a diagnosis of these disorders when classic clinical findings are present. If a muscle biopsy is available, immunostaining may also be an appropriate diagnostic approach.

Telethonin appears to be a rare cause of limb girdle muscular dystrophy and cardiomyopathy. Homozygous or compound heterozygous TCAP variants have been found in three families with members affected with limb girdle muscular dystrophy (Moreira et al. 2000). Among a cohort of 389 HCM patients, four were found to have a TCAP variant (Bos et al. Mol Genet Metab 88:78-85, 2006). In a study of 482 patients (346 with HCM and 136 with DCM) Hayashi et al. found TCAP variants in two patients with HCM and one with DCM (Hayashi et al. J Am Coll Cardiol 44:2192-2201, 2004).

This test provides full coverage of all coding exons of the TCAP gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).