OMIA 001271-9796 : Dwarfism, ACAN-related in Equus caballus

In other species: cattle

Possibly relevant human trait(s) and/or gene(s) (MIM number): 612813

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."

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).

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

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
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

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.
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.

Edit History


  • Created by Frank Nicholas on 27 Jun 2014
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