Integrin Alpha 7-Related Congenital Myopathy via the ITGA7 Gene

Integrin α7β1 is an integral structural component of the sarcolemma that binds laminin, thus connecting the basal lamina to the intracellular space (Muntoni and Voit. Neuromusc Disord 14:635-649, 2004). The integrin alpha 7 gene (ITGA7; OMIM 600536) encodes the α7 subunit of the integrin α7β1 heterodimer. In an Itga7 knockout mouse model, integrin α7β1 was confirmed to be essential in linking the extracellular matrix to the intracellular space of the muscle fiber independently of a similar linkage through the dystrophin-glycoprotein complex (Mayer et al. Nat Genet 17:318-323, 1997). The α7 subunit, which is expressed in skeletal and cardiac muscle (Song et al. J Cell Biol 117:643-657, 1992), may be critical for differentiation and migration processes during myogenesis. Variants in ITGA7 have been found in a small set of patients with congenital myopathy (Hayashi et al. Nat Genet 19:94-97, 1998). Motor milestones were delayed in three reported patients; for example, one child was able to roll over at 9 months of age and walk at 2.5 years but was not able to run or jump. Another could walk independently at 2.1 years and demonstrated a waddling gait and Gower’s sign. This same patient could not run or climb stairs independently. The third child was able to walk at age 5 years but only with support. Other findings in these patients included hypotonia and torticollis from birth and mildly elevated serum CK (163 IU/L, 236 IU/L, 528 IU/L). Cognitive impairment was evident in one of the three patients, although, the etiology was not known. Evaluation of muscle biopsies showed deficient integrin α7 but normal lamin α2, along with mild variation in fiber size, substantial fatty replacement, and little evidence of a dystrophic process.

Congenital myopathy due to integrin α7 deficiency is inherited as an autosomal recessive condition. Three ITGA7 variants, consisting of two splice site variants and one single base deletion, have been reported to date (Hayashi et al. 1998). If a muscle biopsy is available, immunostaining for integrin α7 may also be an appropriate diagnostic approach.

Congenital myopathy due to integrin α7 deficiency is probably a rare disorder. Hayashi et al. (1998) found three cases when they screened 117 patients with unclassified congenital myopathy or congenital muscular dystrophy by immunocytochemistry. The three patients were Japanese.

This test provides full coverage of all coding exons of the ITGA7 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).