Submission Details

AGRN was first reported in relation to autosomal recessive congenital myasthenic syndrome (CMS) in 2009 (Huze et al. PMID: 19631309). Two siblings from a Swiss family presented with childhood onset of mild limb muscle weakness and unilateral ptosis were found to be homozygous for a missense variant in exon 29 of the AGRN gene. Skeletal muscle biopsy showed type I fiber predominance and type II fiber atrophy along with pre- and postsynaptic defects at the neuromuscular junction. Twenty-six variants (twenty-three missense, two nonsense, and one splice-site) that have been reported in eighteen probands in twelve publications (PMIDs: 19631309, 22205389, 24951643, 28937031, 29258548, 31167812, 32221959, 32271162, 32328026, 35670010, 33756069, 36099689) are included in this curation. Patients with AGRN-related CMS are reported to develop muscle weakness with varying severity and progression, mostly of involving proximal or distal limbs, myopathy, ptosis, neuromuscular transmission defects, and rarely respiratory insufficiency requiring support (PMID: 24951643, 32271162). Interestingly, Geremek et al. reported a fetus with fetal akinesis deformation sequence, considered as a severe form of CMS, who harbored a frameshift variant AGRN:c.4657delT (p.C1553fs) in trans with a large deletion involving AGRN as well as other genes (PMID: 31730230). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be dominant negative.

This gene-disease relationship is also supported by animal models and in vitro acetylocholine receptor binding studies (PMIDs: 21890498, 24951643, 32271162). In vitro AChR binding assays in which C2C12 myotubes showed reduced AChR clustering when incubated with conditioned media containing the AGRN variants p.G76S, p.S1180L, p.R1509W, p.G1675S, and p.Y1877D (PMID: 24951643, 32271162). In 1999, Burgess et al. used nerve–muscle cocultures, surgical chimeras, neonatal mutant mice to assess the roles of agrin isoforms in the formation of the NMJ (PMID: 10402191) and concluded agrin promotes presynaptic differentiation by causing the postsynaptic apparatus to produce or localize appropriate retrograde signals (PMID: 10402191). Later, Bogdanik and Burgess reported a mouse model with a homozygous missense mutation (p.Phe1061Ser) in the SEA domain of agrin that replicated neuromuscular symptoms observed in human congenital myasthenic syndrome (PMID 21890498). Agrin has been shown to play an important role in mediation of cell contact-induced acetylcholine receptor clustering with other postsynaptic proteins on muscle fibers and congenital myasthenic syndromes associated with pathogenic variants in* AGRN* alter this crucial function in the formation and maintenance of the neuromuscular junction (PMID: 1659950, 19631309, 22205389).

In summary, there is definitive evidence supporting the relationship between AGRN and autosomal recessive congenital myasthenic syndrome. 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 August 25th, 2025 (SOP Version 11).