Categories: Skeleton phene (incl. short stature & teeth)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 603370 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant + recessive lethal

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2020

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)."

Breed: Munchkin (Cat) (VBO_0100169).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: