Myopathy, Congenital via the TPM3 Gene

Congenital fiber type disproportion (CFTD) is a genetically and clinically heterogeneous congenital myopathy usually presenting as hypotonia and delayed motor milestones before one year of age. Clinical findings among CFTD patients with TPM3 variants include proximal limb girdle weakness, weakness of neck flexion and ankle dorsiflexion, facial weakness, ptosis, and absent or decreased deep tendon reflexes (Clarke et al. Ann Neurol 63:329-337, 2008; Lawlor et al. Hum Mutat 31:176-183, 2010). Dependence on nocturnal ventilation support was a common finding in these two studies and, except for the most severely affected individual, patients remained ambulatory. Age of onset and severity is noted to vary even within the same family (Clarke et al. 2008); however, patients diagnosed as adults through family studies were aware of symptoms of weakness or myalgia as children (Lawlor et al. 2010). Histologically, type 1 muscle fibers from patients were smaller that type 2 fibers by 50% to 77% in one study (Clarke et al. 2008) and 47% in another (Lawlor et al. 2010). Marked fiber size disproportion was due to hypotrophy of type 1 fibers and hypertrophy of type 2 fibers. Typical of CFTD, overall type 1 fiber predominance, absence of type 2B fibers, and absence of other histopathology was commonly observed in patient biopsies (Clarke et al. 2008). Nemaline myopathy (NEM) is a genetically and clinically heterogeneous disorder characterized by muscle weakness, hypotonia, and the presence of rod-like structures called 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 50:312-320, 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 also characterized by type 1 fiber predominance; however, the presence of nemaline bodies is a finding unique to NEM (Ryan et al. Neurol 60:665-673, 2003).

Variants in the gene encoding the muscle form of tropomyosin 3 (TPM3; OMIM 191030), also referred to as alpha-tropomyosin-SLOW, are a rare cause of nemaline myopathy (NEM1; OMIM 609284) and the most common cause of congenital fiber type disproportion (CFTD; OMIM 255310). Myopathy due to TPM3 variants may be inherited as an autosomal dominant or recessive disorder (Lawlor et al. 2010; Clarke et al 2008; Ryan et al. 2001). De novo TPM3 variants have also been documented to cause CFTD (Clarke et al. 2008).

TPM3 variants are the most common known cause of CFTD. Clinical sensitivity should be high when type 1 fiber hypotrophy is >50% in the absence of other histopathological findings. Lawlor et al. (2009) found six of 13 patients with a diagnosis of CFTD based on type 1 fiber hypotrophy to have variants in this gene. In another cohort of 23 CFTD families, six were found to have TPM3 variants (Clarke et al. 2008). It is estimated that TPM3 variants account for <3% of NEM cases (Wattanasirichaigoon et al. Neurol 59:613-617, 2002).

This test provides full coverage of all coding exons of the TPM3 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).