OMIA 000187-9685 : Chondrodysplasia in Felis catus

In other species: dog , pig , cattle

Possibly relevant human trait(s) and/or gene(s) (MIM number): 225500

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant + recessive lethal

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2020

Cross-species summary: Abnormal growth of cartilage, leading to disproportionate dwarfism.

History: Struck et al. (2020): "Munchkin cats were founded on a naturally occurring mutation segregating into long-legged and short-legged types. Short-legged cats showed disproportionate dwarfism (chondrodysplasia) in which all four legs are short and are referred as standard Munchkin cats. Long-legged animals are referred as non-standard Munchkin cats. . . . Munchkin cats have been recognized by The International Cat Association (TICA) as an independent breed since 1994".

Inheritance: Struck et al. (2020): "Breeding data collected by TICA [The International Cat Association] suggest a dominant mode of inheritance . . . and lethality in the homozygous state at an early embryonic stage. . . . Pedigree analysis of the Munchkin cat family of the subtype Genetta demonstrated that three repeated matings between a standard Munchkin tomcat and a standard Munchkin queen resulted in seven standard Munchkin and two non-standard Munchkin cats . . . . As reported by breeders, matings among standard Munchkin cats resulted in reduced litter sizes."

Buckley et al. (2020): "No individuals homozygous for the SV were observed and genotypes were not in Hardy-Weinberg equilibrium (X2 = 23.4, p-value < 0.001). Moreover, out of 11 individuals with two heterozygous affected parents, 7 cats were heterozygous for the SV and 4 cats were homozygous reference, which is consistent with the expected ratio of genotypes for a recessive lethal allele."

Molecular basis: Struck et al. (2020): "Structural variant analysis with LUMPY software revealed one variant on FCA B1 harbouring a heterozygous deletion of 3303 bp in all three standard Munchkin cats but homozygous wild type in the non-standard Munchkin kitten and all 16 controls. The 3303 bp deletion was located within UDP-glucose 6-dehydrogenase (UGDH) at 173,294,289-173,297,592 bp (Felis catus 8.0; NC_018726.2:g.173294289_173297592delins108), equivalent to 174,882,895-174,886,198 bp (Felis catus 9.0; NC_018726.3:g.174882895_174886198delins108) on FCA B1 within the critical region. This 3303 bp deletion comprises 1191 bp of intronic sequences (intron 10–11, ENSFCAT00000009602.6 or intron 9–10, ENSFCAT00000055794.2), exon 11 (ENSFCAT00000009602.6) or 10 (ENSFCAT00000055794.2) and 2001 bp of the 3′-UTR. . . . Sanger cDNA sequencing confirmed the break points of the deletion predicted in the LUMPY software. Furthermore, an insert of 108 bp was identified between the break points of the deletion in all three standard Munchkin cats".

Buckley et al. (2020) independently discovered what appears to be the same likely causal variant of the Munchkin phenotype: "a complex deletion coupled with a nearby potential duplication event that was shared privately across three unrelated cats with dwarfism and is found within a known dwarfism associated region on cat chromosome B1". More specifically, "a 3.3 kb deletion at position chrB1:174,882,897–174,886,198, overlapping the final exon of UDP-glucose 6-dehydrogenase (UGDH) (Fig 4B). Upon manual inspection of this SV, a 49 bp segment from exon 8 appeared to be duplicated and inserted 3.5 kb downstream, replacing the deleted sequence. This potentially duplicated segment was flanked by a 37 bp sequence at the 5`end and a 20 bp sequence at the 3’ end, both of unknown origin".

Clinical features: Struck et al. (2020): "CT of the forelimbs of the 4-year old standard Munchkin tomcat showed a shortening of ​​all distal und proximal long bones including humerus, radius, ulna and metacarpalia (Fig. 2 and Additional file 2). Lengths of the humerus, radius, ulna, metacarpalia, femur and tibia of the standard Munchkin cat were reduced by 71, 58, 64, 84, 74, and 70%, respectively, in comparison to the domestic cat. Metatarsalia had normal length. All bones of the front and hind limbs exhibited higher average diaphyseal diameters, in particular humerus (+ 14%) and femur (+ 29%). Furthermore, the humerus showed a slight internal rotation along its longitudinal axis, resulting in a moderate incongruity in the elbow joint with axial deviation. The humerus compacta in the middle segment revealed a moderate degree of thickening of 2.4 mm (0.09 in). Furthermore, the radius was too short in relation to the ulna, as well as the ulna was slightly medially rotated, whereas the radius was bent to a high degree in the longitudinal axis of about 43°. This resulted in an incongruity in the ulnocarpal and radiocarpal joint. The hind limbs did not show any rotation and structural effects."

Prevalence: Buckley et al. (2020): "PCR-based genotyping of the 3.3 kb deletion breakpoints was conducted in a total of 109 cats including, 41 normal and 68 affected dwarf cats (S9 Fig). Expected amplicon sizes and phenotypes were concordant across all cats, except for a “Munchkin; non-standard (normal legs); Selkirk mix”, which appeared to carry the mutant allele, suggesting an alternate causal gene or sampling error (S8 Data)."

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
UGDH UDP-glucose 6-dehydrogenase Felis catus B1 NC_018726.3 (174853638..174885557) UGDH Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Munchkin Munchkin standard UGDH delins, gross (>20) Felis_catus_9.0 B1 g.174882895_174886198delins108 NC_018726.3:g.174882895_174886198delins108, Felis catus 9.0 (Struck et al., 2020) 2020 32605545

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2020 Buckley, R.M., Davis, B.W., Brashear, W.A., Farias, F.H.G., Kuroki, K., Graves, T., Hillier, L.W., Kremitzki, M., Li, G., Middleton, R.P., Minx, P., Tomlinson, C., Lyons, L.A., Murphy, W.J., Warren, W.C. :
A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism. PLoS Genet 16:e1008926, 2020. Pubmed reference: 33090996. DOI: 10.1371/journal.pgen.1008926.
Lyons, L.A. :
Precision medicine in cats-The right biomedical model may not be the mouse! PLoS Genet 16:e1009177, 2020. Pubmed reference: 33290388. DOI: 10.1371/journal.pgen.1009177.
Struck, A.K., Braun, M., Detering, K.A., Dziallas, P., Neßler, J., Fehr, M., Metzger, J., Distl, O. :
A structural UGDH variant associated with standard Munchkin cats. BMC Genet 21:67, 2020. Pubmed reference: 32605545. DOI: 10.1186/s12863-020-00875-x.
1996 Gunnmoore, D.A., Hagard, G., Turner, C., Duncan, A.W., Barr, F.J. :
Unusual metaphyseal disturbance in two kittens Journal of Small Animal Practice 37:583-590, 1996. Pubmed reference: 8981279.
1988 Latimer, K.S., Rowland, G.N., Mahaffey, M.B. :
Homozygous Pelger-Huët anomaly and chondrodysplasia in a stillborn kitten Vet Pathol 25:325-8, 1988. Pubmed reference: 3407106.

Edit History


  • Created by Frank Nicholas on 06 Sep 2005
  • Changed by Frank Nicholas on 04 Jul 2020
  • Changed by Frank Nicholas on 24 Oct 2020