CHRNB1 was first reported in relation to autosomal dominant Congenital Myasthenic Syndrome (CMS) 2A, slow-channel in 1996 (Engel AG, et al., PMID: 8872460). Congenital myasthenic syndrome associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized clinically by early-onset muscle weakness with variable severity. CMS2A is differentiated by kinetic abnormalities of the acetylcholine receptor channel (AChR), specifically from prolonged opening and activity of the channel, which causes prolonged synaptic currents resulting in a depolarization block. Treatments with cholinesterase inhibitors or amifampridine should be avaided; while treatment with quinine, quinidine, or fluoxetine may be helpful. The clinical features of CMS2A often include easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia).
Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found difference in molecular mechanism and inheritance pattern. Therefore, the following disease entities have been split into multiple disease entities, Myasthenic syndrome, congenital, 2C, associated with acetylcholine receptor deficiency (OMIM:616314 ), and Myasthenic syndrome, congenital, 2A, slow-channel (OMIM:616313 ).
Seven missense variants that have been reported in eleven probands in ten publications (PMIDs: 8872460, 32895905, 29054425, 36099689, 27375219, 16624571, 21822932, 20562457, 14991812, 8651643) are included in this curation. Variants in CHRNB1 result in functional alterations at the neuromuscular junction, primarily through prolonged acetylcholine receptor (AChR) channel openings and increased calcium permeability, leading to cationic overload and synaptic degeneration (PMIDs: 8872460). Expression studies in HEK293 cells demonstrated prolonged channel open times and increased α-bungarotoxin binding for M2 domain variants (PMIDs: 8872460), while patient muscle biopsies revealed focal activation of caspase-3 and -9 at endplates, correlating with ultrastructural abnormalities such as vacuoles and degenerating mitochondria, without overt cell death (PMID: 14991812).
The mechanism of pathogenicity appears to be gain of function. This gene-disease relationship is also supported by expression studies (PMIDs: 29874875, 10562302, 25613900, 8651643, 27375219, 8872460). The Human Protein Atlas (PMID: 25613900) shows CHRNB1 expression enhanced in skeletal muscles. Biochemical functions show that the beta subunit is interactive with the other four, while protein interactions suggests that deletion variants in the beta subunit disrupt the delta subunit (PMID: 29874875, 10562302).
In summary, there is moderate evidence supporting the relationship between CHRNB1 and autosomal dominant Congenital Myasthenic Syndrome (CMS) 2A. This classification was approved by the ClinGen Congenital Myopathies GCEP on the meeting date October 27, 2025 (SOP Version 11).
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