Congenital Myasthenic Syndromes via the CHRNB1 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.

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. CHRNB1 gene variants have been found in patients with slow channel CMS (Engel and Sine Curr Opinion in Pharmacol 5:308-321, 2005). CHRNB1-associated slow channel CMS (OMIM 601462) has been shown to be inherited as a recessive disorder secondary to loss-of-function variants (Quiram et al. J Clin Invest 104:1403-1410, 1999), or as a dominant disorder secondary to gain-of-function variants (Gomez et al. Ann Neurol 39:712-723, 1996; Engel et al. Hum Molec Genet 5:1217-1227, 1996). Null and low expressor CHRNB1 variants in the homozygous or compound heterozygous state lead to CMS with end-plate AChR deficiency (Quiram et al. 1999).

The beta subunit of the acetylcholine receptor is encoded by exons 1 – 11 of the CHRNB1 gene (OMIM 100710) located on chr 17p12.

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). CHRNB1 is a rare cause of CMS.

This test provides full coverage of all coding exons of the CHRNB1 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).