Congenital Myasthenic Syndrome via the MUSK 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. One sibship with CMS and variants in the muscle specific tyrosine kinase (MUSK) gene has been reported (Chevessier et al. Hum Molec Genet 13:3229-3240, 2004). Symptoms of hypotonia, respiratory distress, vocal cord paralysis, and ptosis were present congenitally, and tracheostomies were performed. During childhood and adolescence one sibling experienced exercise-induced fatigue and ptosis, but overall, the course improved with no severe respiratory distress. Symptoms worsened during this patient’s pregnancy. The second patient died in early childhood (Chevessier et al. 2004). Evaluation of a muscle biopsy revealed severe deficiencies in MUSK and CHRNE gene products and remarkable structural abnormalities of the neuromuscular junction.

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. Post synaptic CMS with AChR deficiency (OMIM 608931) is inherited as an autosomal recessive condition and, rarely, is secondary to variants in the MUSK gene (OMIM 601296). The siblings reported by Chevessier et al. (2004) had one null and one missense variant.

The muscle-specific tyrosine kinase is encoded by exons 1 – 15 of the MUSK gene located on chr 9q31.

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). CMS due to MUSK variants is probably a rare disease.

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