Nemaline Myopathy 7 via the CFL2 Gene

Variants in the cofilin-2 gene (CFL2; OMIM 601443) are one cause of autosomal recessive nemaline myopathy (NEM7; OMIM 610687). 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 50:312-320, 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 upon Gomori trichrome staining of skeletal muscle (Ryan et al. Neurology 60:665-673, 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, 2009). CFL2-associated nemaline myopathy is apparently a rare disorder. Two siblings among a large cohort of unrelated NEM patients were found to have a homozygous CFL2 missense variant (Agrawal et al. Am J Hum Genet 80:162-167, 2007). The clinical presentation in the two affected sibs was like that of typical NEM, except facial muscles appeared to be spared and foot drop was not noted. Hypotonia was present at birth, and early motor milestones were delayed. Both patients attained the ability to walk at least short distances but could not run and experienced frequent falls. Muscle biopsies from the patients showed nemaline rods, minicores, type 1 fiber predominance, and marked fiber size variability.

To date, variants in six genes have been shown to cause nemaline myopathy. Variants in ACTA1 (NEM3) and NEB (NEM2) are the only relatively common causes (Ryan et al. 2001). Cofilin-2, a skeletal muscle protein involved with alpha actin assembly, has been found to be mutated in one family (Argawal et al. 2007). NEM7 is inherited as an autosomal recessive disorder secondary to CFL2 variants.

Cofilin-2 associated nemaline myopathy is probably a rare disorder. Argawal et al. (2007) found two sibs with CFL2 gene variants among a cohort of 113 unrelated patients with nemaline myopathy and 58 patients with other forms of congenital myopathy. Another report found no CFL2 variants among a cohort of 50 patients (Thirion et al. Eur J Biochem 268:3473-3482, 2001).

This test provides full coverage of all coding exons of the CFL2 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).