Genes Involved in Congenital Myasthenic Syndromes
At least 35 genes have been identified as causative for congenital myasthenic syndromes, with the acetylcholine receptor subunit genes (CHRNA1, CHRNB1, CHRND, CHRNE) accounting for approximately 50% of all cases. 1
Primary Gene Categories
Postsynaptic Genes (75-80% of CMS cases)
Acetylcholine receptor subunit genes are the most common culprits:
- CHRNA1, CHRNB1, CHRND, CHRNE - encode muscle acetylcholine receptor subunits and represent the single largest group of CMS-causing mutations 2, 3
- CHRNG - encodes the fetal/denervated form of the acetylcholine receptor 1
Other postsynaptic genes:
- RAPSN - accounts for 10-14% of cases when combined with DOK7 and COLQ 3
- DOK7 - represents 10-14% of cases (combined frequency) 3
- MUSK - encodes muscle-specific kinase 3, 1
- LRP4 - encodes low-density lipoprotein receptor-related protein 4 3, 1
Synaptic Genes (14-15% of CMS cases)
- COLQ - encodes the collagen tail of acetylcholinesterase and accounts for 10-14% of cases (combined frequency) 2, 3
- LAMB2 - encodes laminin beta-2 2, 3
- COL13A1 - encodes collagen type XIII alpha-1 1
- LAMA5 - encodes laminin alpha-5 1
Presynaptic Genes (7-8% of CMS cases)
- CHAT - encodes choline acetyltransferase and accounts for approximately 5% of cases 2, 3
- SLC18A3 - encodes vesicular acetylcholine transporter 1
- SLC5A7 - encodes high-affinity choline transporter 1
- SLC25A1 - encodes mitochondrial citrate carrier 1
Synaptic vesicle-related genes:
- SNAP25, SYT2, VAMP1, UNC13A, RPH3A - involved in synaptic vesicle fusion and release 1
Glycosylation Pathway Genes
- GFPT1 - encodes glutamine-fructose-6-phosphate transaminase 1 3, 1
- DPAGT1 - encodes dolichyl-phosphate N-acetylglucosaminephosphotransferase 1 3, 1
- ALG2, ALG14 - involved in protein glycosylation 3, 1
- GMPPB - encodes GDP-mannose pyrophosphorylase B 1
Additional Genes with Diverse Mechanisms
- SCN4A - encodes the voltage-gated sodium channel 2, 3, 1
- AGRN - encodes agrin 3, 1
- PLEC1 - encodes plectin 2, 3, 1
- PREPL - encodes prolyl endopeptidase-like protein 3, 1
- DNM2 - encodes dynamin 2 3
- MTM1 - encodes myotubularin 3
- MYO9A - encodes myosin IXA 1
- TOR1AIP1 - encodes torsin-1A-interacting protein 1 1
- PURA - encodes purine-rich element binding protein A 1
- CHD8 - encodes chromodomain helicase DNA-binding protein 8 1
Critical Clinical Implications
Genetic identification is mandatory because therapeutic responses vary dramatically by gene: acetylcholinesterase inhibitors benefit most CMS subtypes but are contraindicated in others, while ephedrine, salbutamol, and amifampridine show variable efficacy depending on the specific genetic defect 4, 1. Targeted mutation analysis using Sanger or exome sequencing should be guided by characteristic phenotypic features when present 3, as clinical and electrophysiological findings alone cannot reliably identify the causative gene 1.