CHRNE – Congenital Myasthenic Syndrome-4C

Congenital myasthenic syndrome-4C (CMS4C) is an autosomal recessive disorder of the neuromuscular junction caused by deficiency of the adult acetylcholine receptor epsilon subunit encoded by CHRNE. Patients present in infancy with fatigable muscle weakness, motor delay, and fatigue due to impaired neuromuscular transmission (MONDO:0012157).

Inheritance is autosomal recessive, evidenced by three affected siblings in a consanguineous Romani family homozygous for a pathogenic frameshift CHRNE variant, with complete segregation in parents and siblings ([PMID:39941166]). Repetitive nerve stimulation demonstrated a decremental response >10%, confirming a neuromuscular junction defect.

Across the literature, at least 15 probands from ≥9 unrelated families harbor 18 distinct CHRNE variants—including loss-of-function (frameshift, nonsense), missense, and splice-site alleles—segregating in trans with affected status under recessive inheritance ([PMID:10514102], [PMID:16087917], [PMID:29702980]). A representative pathogenic allele is c.295C>T (p.Arg99Ter).

Functional studies in human embryonic kidney cells and Xenopus oocytes have shown that epsilon-subunit frameshift and splice variants markedly reduce surface acetylcholine receptor assembly and channel function, consistent with a loss-of-function mechanism. Retention of intron 11 can partially rescue some deletion alleles but at reduced receptor density ([PMID:10514102], [PMID:16087917]).

No conflicting evidence has been reported. Proteomic and metabolomic profiling in patient blood further reveal biomarker signatures correlating with disease severity, supporting the clinical relevance of CHRNE deficiency.

In summary, robust genetic and experimental data fulfill ClinGen criteria for a Strong gene-disease association. Early genetic diagnosis enables targeted therapy with cholinesterase inhibitors and β2-agonists, improving prognosis and informing carrier screening in at-risk populations.

References

• Diagnostics (Basel, Switzerland) • 2025 • Congenital Myasthenic Syndrome-4C in a Consanguineous Romani Family: Genetic Insights and Clinical Implications. PMID:39941166
• Annals of neurology • 1999 • Novel functional epsilon-subunit polypeptide generated by a single nucleotide deletion in acetylcholine receptor deficiency congenital myasthenic syndrome. PMID:10514102
• Neurology • 2005 • An intronic base alteration of the CHRNE gene leading to a congenital myasthenic syndrome. PMID:16087917
• Medicine • 2018 • CHRNE compound heterozygous mutations in congenital myasthenic syndrome: A case report. PMID:29702980

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