Congenital Myasthenic Syndrome via the COLQ Gene

Congenital myasthenic syndromes (CMS) are disorders of the neuromuscular junction resulting from abnormalities of presynaptic, synaptic, or postsynaptic proteins. CMS are characterized by fatigable weakness affecting limb, ocular, facial, and bulbar muscles. Neonates present with feeding problems, choking, feeble cry, and muscle weakness. Patients presenting in later childhood are seen with abnormal exercise-induced fatigue and difficulty running. Most patients present prior to 2 years of age although rare exceptions are reported (eg. Croxen et al. Neurol 59:162-168, 2002). Symptoms are extremely variable and are in some case induced by febrile illness, infection, or excitement (eg. Byring et al. Neuromuscul Disord 12:548-553, 2002). Life-threatening respiratory crises may occur in affected neonates or older children. CMS may be differentiated from myasthenia gravis, an acquired autoimmune disorder, by earlier age of onset and by negative serology tests for anti-acetylcholine receptor (AchR) and anti-Musk antibodies. CMS with acetylcholinesterase (AChE) deficiency at the synaptic basal lamina has traditionally been differentiated from other forms of CMS clinically by its severe, early-onset phenotype, and pathophysiologically by absence of AChE at the end plate. However, a cohort of end plate acetylcholinesterase deficient patients was recently described with mild clinical presentations similar to those observed in patients with familial limb-girdle CMS in which weakness is primarily found in proximal muscles (Mihaylova et al. Brain 131:747-759, 2008; Müller et al. Neuropediatrics 35:183-189, 2004). Patients with AChE deficiency have been found to be responsive to ephedrine (Mihaylova et al. 2008).

Abnormalities of proteins involved with neuromuscular transmission underlie CMS, limb girdle CMS, Pena-Shokeir syndrome, and multiple pterygium syndromes. These disorders, which may represent a phenotypic continuum of a single entity, are most often inherited in an autosomal recessive manner. Synaptic CMS with acetylcholinesterase deficiency (OMIM 603034) is inherited as an autosomal recessive condition secondary to variants in the COLQ gene (OMIM 603033). Truncating (Ohno et al Proc Natl Acad Sci USA 95:9654-9659, 1998), splice site (Schreiner et al. Neuromusc Disord 17:262-265, 2007), and missense (Müller et al. 2004) variants have been reported. Evidence exists for reduced expression of disease in heterozygous carriers of COLQ variants (Schreiner et al. 2007).

The collagenic tail of the end plate acetylcholinesterase is encoded by exons 1 – 17 of the COLQ gene located on chr 3p25.

Sensitivity for CMS testing is at least 50% overall; 30% for CHRNE, 10% for RAPSN, and 7.5% for COLQ (GeneReviews, Abicht and Lochmüller, 2006).

This test provides full coverage of all coding exons of the COLQ gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.