OMIA 001271-9796 : Dwarfism, ACAN-related in Equus caballus
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 <i>ACAN</i> 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, Shetland. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|ACAN||aggrecan||Equus caballus||1||NC_009144.3 (95320479..95255524)||ACAN||Homologene, Ensembl, NCBI gene|
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|
|Miniature||Dwarfism, ACAN-related||ACAN||D4||deletion, small (<=20)||Ecab 3.0||1||g.95257458_95257500del||p.Phe2017-Asp2023del||rs1095048839||2018||30058072|
|Miniature Shetland||Dwarfism, ACAN-related||ACAN||D3*||missense||Ecab 3.0||1||g.95282140C>G||p.A505P||This variant was named D3* by Eberth et al. (2018)||rs1095048823||2017||27942904||Variant coordinates obtained from Eberth et al. (2018)|
|Miniature||Dwarfism, ACAN-related||ACAN||D2||missense||Ecab 3.0||1||g.95284530C>T||p.Val424Met||2018||30058072|
|Miniature||Dwarfism, ACAN-related||ACAN||D1||deletion, small (<=20)||Ecab 3.0||1||g.95291270del||p.Lys82fx||rs1095048841||2018||30058072|
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||Andrade, D.G.A., Basso, R.M., Castiglioni, M.C.R., Silva, J.P., Machado, V.M.V., Laufer-Amorim, R., Borges, A.S., Oliveira-Filho, J.P. :|
|Description of the D4/D4 genotype in Miniature horses with dwarfism. J Vet Diagn Invest 32:99-102, 2020. Pubmed reference: 31906815. DOI: 10.1177/1040638719898164.|
|Andrade, D.G.A., Basso, R.M., Magro, A.J., Laufer-Amorim, R., Borges, A.S., de Oliveira-Filho, J.P. :|
|Evaluation of a new variant in the aggrecan gene potentially associated with chondrodysplastic dwarfism in Miniature horses. Sci Rep 10:15238, 2020. Pubmed reference: 32943661. DOI: 10.1038/s41598-020-72192-3.|
|2018||Eberth, J.E., Graves, K.T., MacLeod, J.N., Bailey, E. :|
|Multiple alleles of ACAN associated with chondrodysplastic dwarfism in Miniature horses. Anim Genet :, 2018. Pubmed reference: 30058072. DOI: 10.1111/age.12682.|
|2017||Metzger, J., Gast, A.C., Schrimpf, R., Rau, J., Eikelberg, D., Beineke, A., Hellige, M., Distl, O. :|
|Whole-genome sequencing reveals a potential causal mutation for dwarfism in the Miniature Shetland pony. Mamm Genome 28:143-151, 2017. Pubmed reference: 27942904. DOI: 10.1007/s00335-016-9673-4.|
|2014||Bailey, E. :|
|Five things equine veterinarians should know about genomics. Equine Vet J 46:404-7, 2014. Pubmed reference: 24909654. DOI: 10.1111/evj.12271.|
|2013||Eberth, J.E. :|
|Chondrodysplasia-Like Dwarfism in the Miniature Horse. Theses and Dissertations--Veterinary Science. Paper 11. Entire thesis is available at http://uknowledge.uky.edu/gluck_etds/11:, 2013.|
|2009||Eberth, J., Swerczak, T. , Bailey, E. :|
|Investigation of dwarfism Among Miniature Horses using the Illumina Horse SNP50 Bead Chip. Journal of Equine Veterinary Science 29:315 only, 2009.|
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