Submission Details

CHAT was first reported in relation to autosomal recessive Myasthenic syndrome, congenital, 6, presynaptic in 2001 (Ohno K, et al., PMID: 11172068). A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are 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. CMS6 affected individuals have myasthenic symptoms since birth or early infancy, negative tests for anti-AChR antibodies, and abrupt episodic crises with increased weakness, bulbar paralysis, and apnea precipitated by undue exertion, fever, or excitement.

Twenty-four missense, three nonsense, and one frame shift variants that have been reported in eighteen probands and their siblings in eight publications (PMIDs: 11172068, 12756141, 29054425, 12548525, 12609506, 15701560, 19520274, 19900826 ) are included in this curation. Studies of the neuromuscular junction in this disorder showed a stimulation-dependent decrease of the amplitude of the miniature endplate potential and no deficiency of the acetylcholine receptor. These findings pointed to a defect in acetylcholine resynthesis or vesicular filling and to CHAT as one of the candidate genes. These probands primarily share traits of ptosis, generalized muscle weakness, and easy fatiguability and/or exercise intolerance. The most common variant seen was NM_020549.5(CHAT):c.1007T>C (p.Ile336Thr), a missense variant seen mostly inherited as homozygous. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

This gene-disease relationship is also supported by experimental evidence ( animal models, biochemical function) (PMIDs: 17144655, 17144655, 24486622, 12533614, 12441053, 17586598). Several model system studies showed that CHAT disruption in mice causes generalized muscle weakness, abnormal muscle morphology, and ChAT insufficiency similar to that in humans. Though biallelic null variants have not been seen in humans, studies in mice showed lethality. One study concluded CMS in Old Danish Pointing Dogs, based on an electrophysiological test to examine neuromuscular function using repetitive stimulation, showed similar outcomes to the same testing done in humans diagnosed with CMS.

A biochemical functional study shows that communication between cholinergic neurons and their target cells and tissues is dependent on functional ChAT, with the loss of ChAT expression and activity found in several neurological and psychiatric disorders, such as neuromuscular diseases. The ability of ChAT to interact with and acetylate a number of different choline analogues can be rationalized from the mode of choline binding seen in the ChAT-choline complex which helps neuromuscular synaptic transmission.

In summary, there is definitive evidence supporting the relationship between CHAT and autosomal recessive Myasthenic syndrome, congenital, 6, presynaptic. This has been repeatedly demonstrated in 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 March 24th 2025 (SOP Version 11).