title: Whole-genome sequencing reveals a potential causal mutation for dwarfism in the Miniature Shetland pony.
abstract: The Miniature Shetland pony represents a horse breed with an extremely small body size. Clinical examination of a dwarf Miniature Shetland pony revealed a lowered size at the withers, malformed skull and brachygnathia superior. Computed tomography (CT) showed a shortened maxilla and a cleft of the hard and soft palate which protruded into the nasal passage leading to breathing difficulties. Pathological examination confirmed these findings but did not reveal histopathological signs of premature ossification in limbs or cranial sutures. Whole-genome sequencing of this dwarf Miniature Shetland pony and comparative sequence analysis using 26 reference equids from NCBI Sequence Read Archive revealed three probably damaging missense variants which could be exclusively found in the affected foal. Validation of these three missense mutations in 159 control horses from different horse breeds and five donkeys revealed only the aggrecan (ACAN)-associated g.94370258G>C variant as homozygous wild-type in all control samples. The dwarf Miniature Shetland pony had the homozygous mutant genotype C/C of the ACAN:g.94370258G>C variant and the normal parents were heterozygous G/C. An unaffected full sib and 3/5 unaffected half-sibs were heterozygous G/C for the ACAN:g.94370258G>C variant. In summary, we could demonstrate a dwarf phenotype in a miniature pony breed perfectly associated with a missense mutation within the ACAN gene.
authors.affiliation: Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, 30559, Hannover, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Metzger
authors.affiliation: Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, 30559, Hannover, Germany.
authors.forename: Alana Christina
authors.initials: AC
authors.lastname: Gast
authors.affiliation: Unit of Reproductive Medicine of the Clinics, University of Veterinary Medicine Hannover, 30559, Hannover, Germany.
authors.forename: Rahel
authors.initials: R
authors.lastname: Schrimpf
authors.affiliation: Unit of Reproductive Medicine of the Clinics, University of Veterinary Medicine Hannover, 30559, Hannover, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Rau
authors.affiliation: Department of Pathology, University of Veterinary Medicine Hannover, 30559, Hannover, Germany.
authors.forename: Deborah
authors.initials: D
authors.lastname: Eikelberg
authors.affiliation: Department of Pathology, University of Veterinary Medicine Hannover, 30559, Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beineke
authors.affiliation: Clinic for Horses, University of Veterinary Medicine Hannover, 30559, Hannover, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Hellige
authors.affiliation: Institute for Animal Breeding and Genetics, University of Veterinary Medicine Hannover, 30559, Hannover, Germany. ottmar.distl@tiho-hannover.de.
authors.forename: Ottmar
authors.initials: O
authors.lastname: Distl
mesh_terms: D053674:Aggrecans / Q000235:genetics*; D000818:Animals; D001947:Breeding; D004392:Dwarfism / Q000235:genetics* / Q000503:physiopathology; D005838:Genotype; D006720:Homozygote; D006734:Horse Diseases / Q000235:genetics* / Q000503:physiopathology; D006736:Horses / Q000235:genetics* / Q000254:growth & development; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D000073336:Whole Genome Sequencing
chemical_list: D053674:Aggrecans