In other species: taurine cattle , indicine cattle (zebu)

Categories: Skeleton phene (incl. short stature & teeth) , Growth / size / body region phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 612813 (trait) , 165800 (trait) , 608361 (trait) , 155760 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2017

Mapping: By conducting a GWAS on 20 dwarf and 26 control Miniature horses, each of which had been genotyped with the Illumina Equine SNP50 chip (yielding 40,368 informative SNPs), Eberth (2013) mapped this disorder to a region on chromosome ECA1.

Molecular basis: Noting that the relevant region of chromosome ECA1 contains the ACAN gene that has been implicated in similar types of dwarfism in cattle (see OMIA 001271-9913) and humans (see MIM entry above), Eberth (2013) sequenced this comparative positional candidate gene in affected and normal Miniature horses, revealing four variants strongly associated with dwarfism: c.245del, p.K82fx in exon 2 (Acan-D1); c.1270G>A, p.V424M in exon 6 (Acan-D2); c.6700delC, p.P1875fx in exon 11 (Acan-D3); c.7299-7319del, p.F2433-O2440del in exon 15 (Acan-D4). Bailey (2014) mentioned Eberth's discovery, but made no mention of any specific likely causal variant. Metzger et al. (2017) reported a missense mutation (g.94370258G>C; p.A505P) as a likely causal variant in a "Miniature Shetland". Eberth's 2013 thesis results were published by Eberth et al. (2018), who reported four likely causal variants, namely "g.95291270del (rs1095048841), g.95284530C>T (ERP107353), g.95282140C>G (rs1095048823) and g.95257480_95257500del (rs1095048839)", all with respect to Ecab 3.0 (GCF_002863925.1), naming them D1, D2, D3*, and D4, respectively. As these authors noted, D3* is the same variant reported by Metzger et al. (2017). As explained by Eberth et al. (2018), D3* is given an asterisk to differentiate it from the original D3 allele described by Eberth (2013), a deletion in exon 11, which turned out to be a technical artifact. Ebert et al. (2018) reported that "Homozygotes for those variants and compound heterozygotes for any combination of those variants always expressed a dwarfism phenotype. However, eight additional horses with dwarfism were found, seven of which were heterozygotes for D2, D3* or D4 [and the other dwarf did not possess any of these variants], suggesting the existence of additional ACAN alleles causing dwarfism." Andrade et al. (2020; PMID 32943661) reported a fifth variant, namely a "missense SNP in coding exon 11 (g.95271115A > T, c.6465A > T-RefSeq XM_005602799.2), which resulted in the amino acid substitution p.Leu2155Phe (RefSeq XP_005602856.2)" that could be "a marker of disequilibrium or complex interactions in the Miniature horse genome could contribute to the associated dwarfism".

Clinical features: "Chondrodysplastic dwarfism in horses was identified based on severely shortened stature relative to horses of that age plus any of the following characteristics: shortened limbs relative to overall body size, bowed forelegs, shortened neck, disproportionately large cranium, compressed faces with large bulging eye sockets with prominent eyes, low nasal bridge, severe underbite, retruded muzzle, cleft palate and protruding tongue, a large abdominal hernia or embryonic loss with a dwarf phenotype of the fetus." (Eberth et al., 2018). Andrade et al. (2020; PMID 31906815) reported the first documented cases of homozygosity for the D4 variant: "2 Miniature horses with the genotype D4/D4 in the ACAN gene. Clinically, the 2 dwarfs had a domed head that was large compared to the rest of the body, mandibular prognathism, and short and bowed limbs, mainly in the proximal region of the metatarsal bones. Radiographic examination revealed contour irregularities of the subchondral bone in the long bones and confirmed mandibular prognathism; histopathology revealed irregular chondrocyte organization."

Prevalence: Eberth et al. (2018) reported the frequencies in Minatures of each variant were 0.03 for D1, 0.09 for D2, 0.02 for D3* and 0.03 for D4.

Breeds: Miniature Horse (Horse) (VBO_0016848), Shetland Pony (Horse) (VBO_0001066).
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: