title: Deletion of 2.7 kb near HOXD3 in an Arabian horse with occipitoatlantoaxial malformation.
abstract: In the horse, the term occipitoatlantoaxial malformation (OAAM) is used to describe a developmental defect in which the first cervical vertebra (atlas) resembles the base of the skull (occiput) and the second cervical vertebra (axis) resembles the atlas. Affected individuals demonstrate an abnormal posture and varying degrees of ataxia. The homeobox (HOX) gene cluster is involved in the development of both the axial and appendicular skeleton. Hoxd3-null mice demonstrate a strikingly similar phenotype to Arabian foals with OAAM. Whole-genome sequencing was performed in an OAAM-affected horse (OAAM1) and seven unaffected Arabian horses. Visual inspection of the raw reads within the region of HOXD3 identified a 2.7-kb deletion located 4.4 kb downstream of the end of HOXD4 and 8.2 kb upstream of the start of HOXD3. A genotyping assay revealed that both parents of OAAM1 were heterozygous for the deletion. Additional genotyping identified two of 162 heterozygote Arabians, and the deletion was not present in 371 horses of other breeds. Comparative genomics studies have revealed that this region is highly conserved across species and that the entire genomic region between Hoxd4 and Hoxd3 is transcribed in mice. Two additional Arabian foals diagnosed with OAAM (OAAM 2 and 3) were genotyped and did not have the 2.7-kb deletion. Closer examination of the phenotype in these cases revealed notable variation. OAAM3 also had facial malformations and a patent ductus arteriosus, and the actual malformation at the craniocervical junction differed. Genetic heterogeneity may exist across the HOXD locus in Arabian foals with OAAM.
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Bordbari
authors.affiliation: Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616, USA.
authors.forename: M C T
authors.initials: MCT
authors.lastname: Penedo
authors.affiliation: Department of Veterinary Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616, USA.
authors.forename: M
authors.initials: M
authors.lastname: Aleman
authors.affiliation: Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, 48824, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Valberg
authors.affiliation: Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, 55108, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mickelson
authors.affiliation: Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, CA, 95616, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Finno
mesh_terms: D000818:Animals; D005260:Female; D005801:Genes, Homeobox; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006734:Horse Diseases / Q000235:genetics*; D006736:Horses / Q000235:genetics*; D008297:Male; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: D018398:Homeodomain Proteins
keywords: atlas; axis; cervical; equine; homeobox, whole-genome sequencing