ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000001.10) (NC_000001.11)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
23253743 Petersen, et al. (2012) report a 3 1/2 year old male who presented with autism features, intellectual disabilities, strabismus, and cranial nerve VI palsy. He had a prominent nasal bridge and behavior problems. The patient was found to carry a 473 kb deletion that removed the first four exons of CHRM3. No functional/expression studies were performed to determine whether the mutant CHRM3 allele retained any residual activity and parental studies were not available.

Haploinsufficiency phenotype comments:

CHRM3 encodes for the M3-muscarinic receptor, which is one of five G protein-linked 7-transmembrane muscarinic receptors expressed in the CNS and peripheral tissues. At this time there is little evidence for haploinsufficiency of CHRM3. Current evidence includes one intragenic deletion in CHRM3, which removes the first four exons of CHRM3 (Petersen et al. 2012), as well as a small non-focal deletion (911 kb) that encompasses all of CHRM3 and most of FMN2 (Perrone et al. 2011). Shared phenotypic findings between the two patients in these studies include autistic features, intellectual disabilities, and strabismus. The patient carrying the 911 kb deletion presented with additional phenotypic abnormalities including cryptorchidism and short stature. However, Weber et al. (PMID:22077972) report a Turkish family with 6 male siblings affected by prune belly-like features. Two had full prune belly syndrome, 4 had bladder malformations, and 3 had posterior urethral valves. They all also had bilaterally impaired pupillary constriction to light and dry mouths. Affected individuals were homozygous for a frameshift mutation in CHRM3. The unaffected parents and sister were heterozygous and the variant was not found in 374 Turkish control chromosomes. Authors comment that this phenotype is consistent with a null mouse model. Furthermore, Lin et al. (PMID:22899762) investigated possible associations between copy number variation involving the CHRM genes (including CHRM3) and high myopia in two different groups of Han Chinese medical students. Using qPCR, no associations with copy loss were found but they did report 23 of the 519 total subjects (4.4%) who had a single copy of CHRM3. Given the current limited and contradictory evidence for CHRM3 haploinsufficiency, the haploinsufficiency score for this gene is a 1.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Reports of focal duplications of CHRM3 have not been reported in clinical patients. Lin, et al., (PMID:22899762) report a significant association between copy number gains (3-5 copies) of CHRM3 and high myopia in Han Chinese medical students, indicating that gain of CHRM3 may be a risk factor for high myopia.