Multiocular Defect in the Old English Sheepdog: A canine form of Stickler syndrome type II associated with a missense variant in the collagen-type Gene COL11A1

Presenter Katherine Stanbury
Authors Stanbury, K.(1), Stavinohova, R.(2), Pettitt, L.(1), Dixon, C.(3), Schofield, E.C.(1), Mclaughlin, B.(1), Pettinen, I.(4), Lohi, H.(4), Ricketts, S.L.(1), Oliver, J.A.(5), Mellersh, C.S.(1)
Affiliations (1) Kennel Club Genetics Centre, Department of Veterinary Medicine, University of Cambridge, UK, (2) Lumbry Park Veterinary Specialists, UK, (3) Veterinary Vision, UK, (4) Department of Veterinary Biosciences, Department of Medical and Clinical Genetics, University of Helsinki and Folkhälsan Research Center, 00014 Helsinki, Finland, (5) Dick White Referrals, UK
Presentation Type Talk


Multiocular defect (MOD) has been described in different canine breeds, including the Old English Sheepdog, with an unknown mode of inheritance. Affected dogs typically present with multiple and various ocular abnormalities. Our objectives were to describe the clinical presentation of MOD in the OES and use whole genome sequence (WGS) analysis to identify the causal variant. We carried out WGS on an Old English Sheepdog that had been diagnosed with hereditary cataracts at the age of five and then referred to a board-certified veterinary ophthalmologist due to owner-reported visual deterioration. An ophthalmic assessment revealed that there was bilateral vitreal degeneration, macrophthalmos, and spherophakia in addition to cataracts. Follow-up consultations revealed cataract progression, retinal detachment, uveitis and secondary glaucoma. Whole genome sequence filtered variants private to the case, shared with another Old English Sheepdog genome and predicted to be deleterious were genotyped in an initial cohort of six Old English Sheepdogs (three MOD- affected and three control dogs without evidence of inherited eye disease). Only one of the twenty-two variants segregated correctly with the disease. The variant is a single nucleotide substitution, located in the collagen-type gene COL11A1, c.1775T>C, that causes an amino acid change, p.Phe1592Ser. Genotyping of an additional 14 MOD-affected Old English Sheepdogs revealed a dominant mode of inheritance with four cases heterozygous for the variant. Further genotyping of hereditary cataract-affected Old English Sheepdogs revealed segregation of the variant in eight out of nine dogs. The dog homozygous for the reference allele was diagnosed with congenital hereditary cataracts at two months old. Variants in the COL11A1 gene are causal for Stickler syndrome, Marshall syndrome and Kniest dysplasia in humans. Stickler syndrome type II shares the most analogous clinical features with MOD in the OES.