Categories: Digestive / alimentary phene

Possibly relevant human trait(s) and/or gene(s) (MIM number): 606111 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2022

Species-specific name: congenital idiopathic megaesophagus, CIM

Species-specific symbol: CIM

Mapping: By conducting a GWAS on 19 affected and 177 control German Shepherd dogs, each genotyped with the Affymetrix v2 canine SNP chip (Yielding 48,415 SNPs for the analysis), Tsai et al. (2012) highlighted a 4.7Mb region on chromosome CFA12. Bell et al. (2022) also highlighted a region in CFA12: "A genome-wide association study for CIM revealed an association on canine chromosome 12 (P-val = 3.12x10-13), with the lead SNPs located upstream or within Melanin-Concentrating Hormone Receptor 2 (MCHR2), a compelling positional candidate gene having a role in appetite, weight, and GI motility." It is not evident whether this region overlaps the region highlighted by Tsai et al. (2012).

Molecular basis: Bell et al. (2022): "Within the first intron of MCHR2, we identified a 33 bp variable number tandem repeat (VNTR) containing a consensus binding sequence for the T-box family of transcription factors. Across dogs and wolves, the major allele includes two copies of the repeat, whereas the predominant alleles in GSDs have one or three copies. The single-copy allele is strongly associated with CIM [Congenital idiopathic megaesophagus] (P-val = 1.32x10-17), with homozygosity for this allele posing the most significant risk. Our findings suggest that the number of T-box protein binding motifs may correlate with MCHR2 expression and that an imbalance of melanin-concentrating hormone plays a role in CIM.

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Prevalence: Bell et al. (2022) reported "that male GSDs are twice as likely to be affected as females and show that the sex bias is independent of body size. We propose that female endogenous factors (e.g., estrogen) are protective via their role in promoting relaxation of the sphincter between the esophagus and stomach, facilitating food passage".

Control: Bell et al. (2022): "Together, sex and the MCHR2 repeat sequence accurately predict affection status in over 75% of dogs, and a genetic test is now available to facilitate breeding decisions aimed at reducing disease incidence."

Breed: German Shepherd Dog (Dog) (VBO_0200577).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: