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Whole-genome sequencing reveals a potential causal mutation for dwarfism in the Miniature Shetland pony


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.

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The authors are grateful to all horse breeders donating samples and providing data for this research project. The authors thank Dr. R. Geffers and S. Buhju at the Helmholtz Centre for Infection Research in Braunschweig for their support in library preparation. We also thank J. Wrede for his help in data analysis and M. Drabert for his support in DNA isolation.

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Correspondence to Ottmar Distl.

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Metzger, J., Gast, A.C., Schrimpf, R. et al. Whole-genome sequencing reveals a potential causal mutation for dwarfism in the Miniature Shetland pony. Mamm Genome 28, 143–151 (2017).

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  • Osteochondritis Dissecans
  • Epiphyseal Plate
  • Dwarf Phenotype
  • ACAN Gene
  • NCBI Sequence Read Archive