Compton-North Congenital Myopathy via the CNTN1 Gene

Compton-North congenital myopathy (OMIM 612540) is a severe, congenital myopathy with fetal akinesia and distinct secondary losses of beta-2-syntrophin and alpha-dystrobrevin observed in muscle biopsy.  Among a large cohort of patients with myopathies of unknown etiology, Jones et al. (Neuromusc Disord 13:456-467, 2003) found a small subset of patients with deficiencies of one or more components of the syntrophin–dystrobrevin subcomplex, a part of the dystrophin-glycoprotein complex which anchors the extracellular matrix to the intracellular cytoskeleton of muscle cells.  An affected sibship in this group of patients was further studied by Compton et al. (Am J Hum Genet 83:714-724, 2008).  Clinical findings in the affected sibship included reduced fetal movement, polyhydramnios, premature birth, severe hypotonia, absent deep tendon reflexes, and skeletal, bulbar, and respiratory weakness (Compton et al. 2008; Jones et al. 2003).  One patient survived to one month of age with intubation while the remaining three died shortly after birth.  Dysmorphic features were also reported.  These included scaphocephaly, an oval-shaped face, hypertelorism, and a high-arched palate. Findings of the hands and fingers included simian creases, arachnodactyly, overlapping fingers, and camptodactyly.  Serum CpK levels were normal.  Skeletal muscle biopsy showed myopathic changes including minor variation in fiber size, and there was no indication of dystrophic changes.  Immunohistochemical and western blot analysis revealed decreased or absent beta-2-syntrophin and alpha-dystrobrevin at the muscle sarcolemma (Compton et al. 2008).  Genetic analysis ruled-out mutations in the genes encoding these proteins (Jones et al. 2003) and, instead, homozygous mutations in the contactin-1 (CNTN1) gene were found (Compton et al. 2008).

Compton-North congenital myopathy is inherited as an autosomal recessive disorder.  Thus far only one family has been diagnosed with CNTN1 mutations.  Affected members of the reported family were found to be homozygous for a frame-shift mutation (Compton et al. 2008). Contactin-1, a neural immunoglobulin family adhesion protein, is expressed at the neuromuscular junction as well as in the central and peripheral nervous system.  It has been proposed that loss of contactin-1 at the neuromuscular junction impairs communication or adhesion between nerve and muscle leading to defective neuromuscular transmission, similar to that seen in congenital myasthenic syndrome (Compton et al. 2008).

Thus far Compton-North congenital myopathy has been diagnosed molecularly in a single sibship from consanguineous parents of Egyptian origin (Compton et al. 2008). Clinical and analytical sensitivity cannot be estimated due to the paucity of reported cases.

This test provides full coverage of all coding exons of the CNTN1 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).