Congenital Myasthenic Syndrome with Episodic Apnea via the CHAT 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 cases 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 at onset and by negative serology tests for anti-acetylcholine receptor (AchR) and anti-Musk antibodies. CMS with choline acetyltransferase variants can be differentiated from other forms of CMS clinically by the occurrence of apnea, and pathophysiologically by its effects at the presynaptic membrane.

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. Presynaptic CMS with episodic apnea (OMIM 254210) is inherited as an autosomal recessive condition secondary to variants in CHAT (OMIM 118490). Variants result in null alleles or reduced CHAT expression (Ohno et al. Proc Natl Acad Sci USA 98:2017-2022, 2001), or affect the substrate binding or catalytic sites of the enzyme (Cai et al. EMBO J 23:2047-2058, 2004).

Choline acetyltransferase is encoded by exons 1 – 15 of the CHAT gene located on chr 10q11.

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). Clinical sensitivity should be high for cases with episodic apnea.

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