OMIA:001271-9796 : Dwarfism, ACAN-related in Equus caballus
In other species: taurine cattle
Categories: Skeleton phene (incl. short stature & teeth)
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 612813 (trait) , 165800 (trait) , 608361 (trait) , 155760 (gene)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: 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 <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 Horse (Horse) (VBO_0016848), Shetland Pony (Horse) (VBO_0001066).
|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|
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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.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|1001||Miniature Horse (Horse)||Dwarfism, ACAN-related||ACAN||D4||deletion, small (<=20)||Naturally occurring variant||EquCab3.0||1||g.95257480_95257500del||c.7633_7653del||p.(F2545_D2551del)||220110: corrected genomic position from g.95257458_95257500del to 95257480_95257500 and updated cDNA and published protein coordinates (p.(F2017_D2023del)) based on the following transcripts: ENSECAT00000040213.1:c.7633_7653del ENSECAP00000032890.1:p.Phe2545_Cys2551del||rs1095048839||2018||30058072|
|788||Miniature Horse (Horse) Shetland Pony (Horse)||Dwarfism, ACAN-related||ACAN||D3*||missense||Naturally occurring variant||EquCab3.0||1||g.95282140C>G||c.1513G>C||p.(A505P)||ENSECAT00000040213.1:c.1513G>C ENSECAP00000032890.1:p.Ala505Pro This variant was named D3* by Eberth et al. (2018)||rs1095048823||rs1095048823||2017||27942904||Variant coordinates obtained from Eberth et al. (2018) and EVA_ID link|
|1000||Miniature Horse (Horse)||Dwarfism, ACAN-related||ACAN||D2||missense||Naturally occurring variant||EquCab3.0||1||g.95284530C>T||p.(V424M)||rs3091781465||2018||30058072|
|999||Miniature Horse (Horse)||Dwarfism, ACAN-related||ACAN||D1||deletion, small (<=20)||Naturally occurring variant||EquCab3.0||1||g.95291271del||c.245del||p.(K82Rfs*54)||220110: changed g.95291270del to g.95291271del based on HGVS 3'rule. ENSECAT00000040213.1:c.245del ENSECAP00000032890.1:p.Lys82ArgfsTer54||rs1095048841||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.|
|Graves, K.T., Eberth, J.E., Bailey, E. :|
|Heterozygotes for ACAN dwarfism alleles in horses have reduced stature. Anim Genet 51:420-422, 2020. Pubmed reference: 32065671 . DOI: 10.1111/age.12921.|
|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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