Submission Details

CHRNB1 was first reported in relation to autosomal recessive Congenital Myasthenic Syndrome (CMS) 2C in 1999 (Quiram et al., PMID: 10562302). 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. CMS2C is differentiated by deficiency of AChR at the endplate resulting in low amplitude of the miniature endplate potential and current. Treatments with cholinesterase inhibitors or amifampridine may be helpful. The clinical features of CMS2C 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). The symptoms fluctuate and worsen with physical effort.

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 ).

Twelve variants (missense, in-frame indel, nonsense, large deletion) that have been reported in seven probands in six publications (PMIDs: 32504635, 26633542, 33060286, 33296147, 10562302) and ClinVar (SCV004047718.1) are included in this curation. Common to many of the probands is an exon 8 skipping. This is either a compound heterozygous variation (typically inherited from mom) with another variant in CHRNB1, or in one case (PMID: 33060286) homozygous inheritance with both parents known carriers. Quiram et al, 1999 also showed functional evidence of the patient's intercostal muscle. When compared the number of iodine-125 labeled alpha-bungarotoxin, used to identify and quantify the number of nicotinic acetylcholine receptors (nAChRs) that bind α-Bgt, per end-plate was less than 3% of the normal adult value and less than 7% of the value obtained in a 3-year-old control (PMID: 10562302).

The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by animal models, and expression studies (PMIDs: 10562302, 27364156, 17959719, 25613900, 29874875). The Human Protein Atlas (PMID: 25613900) shows CHRNB1 expression enhanced in skeletal muscles. Mouse models show abnormal muscle development and movement when the beta subunit has variants present, consistent with CMS2C (PMID: 17959719). While cattle models show widespread contracture of joints, muscle weakness, and degradation of NMJ. Bovine familial arthrogryposis multiplex congenita (AMC) represents an inherited neuromuscular disorder corresponding to human CMS (PMID: 27364156). 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 definitive evidence supporting the relationship between CHRNB1 and autosomal recessive Congenital Myasthenic Syndrome (CMS) 2C. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathies GCEP on the meeting date July 28, 2025 (SOP Version 11).