Congenital Myasthenic Syndrome via the SYT2 Gene

Congenital myasthenic syndromes (CMS) are disorders of the neuromuscular junction resulting from abnormalities of presynaptic, synaptic, or post synaptic 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 have been reported (Croxen et al. 2002). Symptoms are extremely variable, and are in some case induced by febrile illness, infection, or excitement (Byring et al. 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, such as anti-acetylcholine receptor (AchR) and anti-Musk antibodies (Engel et al. 2015). CMS can be classified based on the location of the defect: presynaptic, synaptic, and postsynaptic. Congenital myasthenic syndrome-7 (CMS7) is potentially treatable complex presynaptic congenital myasthenic syndrome resulting from pathogenic variants in the SYT2 gene (Herrmann et al. 2014).

Congenital myasthenic syndrome-7 is caused by pathogenic variants in SYT2 and is inherited in autosomal dominant manner. The SYT2 gene encodes a synaptic vesicle membrane protein, which is an important calcium sensor and plays critical role in vesicular trafficking and exocytosis. The SYT2 gene contains nine exons (eight coding exons), encodes 419 amino acids and located at 1q32.1. Pathogenic variants in SYT2 disrupt synaptic vesicle exocytosis in a dominant-negative manner and interfere calcium-triggered neurotransmitter release in peripheral motor nerve terminals (Herrmann et al. 2014; Whittaker et al. 2015).

Clinical sensitivity is not available because only a limited number of patients have been reported. The majority of reported pathogenic variants in SYT2 are missense, although one large duplication has been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SYT2 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).