Tropomyosin 2-Related Disorders via the TPM2 Gene

Mutations in TPM2 cause several distinct myopathic disorders (Tajsharghi et al. Neuromuscul Disord 22(11):923-933, 2012).

Nemaline myopathy (NEM) is a genetically and clinically heterogeneous disorder characterized by muscle weakness, hypotonia and the presence of nemaline bodies in skeletal muscle fibers. Muscle weakness is typically observed in affected neonates or infants, although later onset cases are reported (Ryan et al. Ann Neurol 50(3):312-320, 2001). The most severely affected muscle groups are proximal limb, facial, bulbar, and respiratory muscles. Deep tendon reflexes are absent or depressed. Histologically, NEM is characterized by type 1 fiber predominance and the presence of rod-like structures called nemaline bodies with Gomori trichrome staining of skeletal muscle (Ryan et al. Neurol 60(4):665-673, 2003). Six clinical types of NEM have been delineated based on age of onset, severity and distribution of weakness, and respiratory function (Ryan et al. 2001; North and Ryan. GeneReviews, 2012). Overlap among the six groups is significant, and adults are sometimes diagnosed only after a family member has presented with typical signs.

Distal arthrogryposis syndromes (DA) are a group of multiple congenital contracture disorders with distal joint involvement more common than proximal; variable clinical expression; and autosomal dominant inheritance (Bamshad et al. Am J Med Genet 65(4):277-281, 1996). Distal arthrogryposis type 1 (DA1) is characterized by talipes and camptodactyly, although the shoulders and hips may also be affected (Sung et al. Am J Hum Genet 72(3):681-690, 2003). The clinical phenotype of DA1 overlaps that of Freeman-Sheldon syndrome (FSS; Klemp and Hall. Am J Med Genet 55(4):414-419, 1995), and individuals with features in common to both DA1 and FSS have been found to have mutations in the TNNI2 gene (Sung et al., 2003). Autosomal dominant trismus-pseudocamptodactyly syndrome (distal arthrogryposis type 7, OMIM 158300) was previously thought to be caused by MYH8 gene mutations alone, however, a TPM2 mutation has been found to be causative for this disorder (Davidson et al. 2013 Brain 136 (Pt 2): 508–521).

An autosomal dominant distal myopathy with both cores and rods on muscle biopsy has also been associated with a TPM2 mutation in one family (Davidson et al., 2013).

Tropomyosin 2 (TPM2; OMIM 190990) encodes the muscle isoform of tropomyosin 2, a regulator of actin-myosin interactions. TPM2-related myopathies are inherited as autosomal dominant disorders. Amino acid substitutions are the largest class of TPM2 mutations. An N-terminal amino acid deletion (p.Lys7del) has been found to be causative for a range of clinical phenotypes (Davidson et al., 2013: Mokbel et al. Brain 136(Pt 2): 494-507). Somatic mosaicism for a TPM2 mutation in an unaffected parent has been documented (Tasca et al. Acta Neuropathy 125(1):169-171, 2013).

TPM2 mutations are a rare cause of nemaline myopathy and distal arthrogryposis. In a cohort of 66 unrelated nemaline myopathy patients, two were found to have TPM2 mutations (Donner et al. Neuromuscul Disord 12(2):151-158, 2002). One family with distal arthrogryposis has been found with a TPM2 mutation (Sung et al. Am J Hum Genet 72(3): 681-690, 2003).

Thus far, no gross deletions or duplications have been reported in TPM2 (Human Gene Mutation Databse).

This test provides full coverage of all coding exons of the TPM2 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).