Clinical, histopathological and genetic characterisation of oculoskeletal dysplasia in the Northern Inuit Dog

Abstract

Seven Northern Inuit Dogs (NID) were diagnosed by pedigree analysis with an autosomal recessive inherited oculoskeletal dysplasia (OSD). Short-limbed dwarfism, angular limb deformities and a variable combination of macroglobus, cataracts, lens coloboma, microphakia and vitreopathy were present in all seven dogs, while retinal detachment was diagnosed in five dogs. Autosomal recessive OSD caused by COL9A3 and COL9A2 mutations have previously been identified in the Labrador Retriever (dwarfism with retinal dysplasia 1— drd1 ) and Samoyed dog (dwarfism with retinal dysplasia 2— drd2 ) respectively; both of those mutations were excluded in all affected NID. Nine candidate genes were screened in whole genome sequence data; only one variant was identified that was homozygous in two affected NID but absent in controls. This variant was a nonsense single nucleotide polymorphism in COL9A3 predicted to result in a premature termination codon and a truncated protein product. This variant was genotyped in a total of 1,232 dogs. All seven affected NID were homozygous for the variant allele ( T/T ), while 31/116 OSD-unaffected NID were heterozygous for the variant ( C/T ) and 85/116 were homozygous for the wildtype allele ( C/C ); indicating a significant association with OSD ( p = 1.41x10 -11 ). A subset of 56 NID unrelated at the parent level were analysed to determine an allele frequency of 0.08, estimating carrier and affected rates to be 15% and 0.6% respectively in NID. All 1,109 non-NID were C/C , suggesting the variant is rare or absent in other breeds. Expression of retinal mRNA was similar between an OSD-affected NID and OSD-unaffected non-NID. In conclusion, a nonsense variant in COL9A3 is strongly associated with OSD in NID, and appears to be widespread in this breed.

Identification of a variant in NDP associated with X-linked retinal dysplasia in the English cocker spaniel dog

“…It has been described in multiple dog breeds and can be subdivided into focal, multifocal, geographic and total retinal dysplasia types [2]. RD can present as a nonsyndromic form such as that described in the Bedlington and Sealyham Terriers or it can present as a syndromic RD such as in oculoskeletal dysplasia described in the Labrador Retriever, Samoyed and Northern Inuit dog [3][4][5][6][7]. Genetic variants associated with oculoskeletal dysplasia have been identified in all of these breeds [7,8].…”

“…The genetic variant for CEA has been identified in non-homologous end joining factor 1 ( NHEJ1 ) [ 11 ]. The mode of inheritance of total RD and CEA has been reported to be autosomal recessive in all breeds [ 3 , 4 , 7 , 8 , 10 ]. Although other retinal pathologies have been found to be X-linked in dogs, such as XLPRA in the Siberian Husky as well as other breeds, to the author’s knowledge an X-linked RD has not been reported before [ 12 ].…”

Cataracts and phacoemulsification in the Siberian Husky: A retrospective and multicentric study (2008–2018)

“…In contrast, a recent study found no significant differences between the four stages of cataracts and surgical complications 35 . Microphakia has been described concurrently with retinal detachment in dogs with oculoskeletal dysplasia; however, a causal relationship has not been identified 36 . The authors of this manuscript consider that microphakia or lens resorption may result in difficulty placing an IOL intraoperatively, with the potential for capsular tears and/or vitreal traction bands resulting in rhegmatogenous retinal detachment.…”

“…35 Microphakia has been described concurrently with retinal detachment in dogs with oculoskeletal dysplasia; however, a causal relationship has not been identified. 36 The authors of this manuscript consider that microphakia or lens resorption may result in difficulty placing an IOL intraoperatively, with the potential for capsular tears and/or vitreal traction bands resulting in rhegmatogenous retinal detachment. In this study, 9% of Husky eyes with an IOL placed had post-operative retinal detachments compared to the non-Husky eyes, in which no eyes with an IOL placed had postoperative retinal detachment.…”

Oculo‐skeletal dysplasia in five Labrador Retrievers

“…Oculo‐skeletal dysplasia (OSD) is a rare genetic syndrome reported in Labrador Retriever, Samoyed and Northern Inuit dogs, characterized by various ocular abnormalities combined with osteochondrodysplasia . Ocular defects described in OSD include cataracts, persistent hyperplastic primary vitreous (PHPV), vitreous syneresis, retinal dysplasia, retinal separation, and retinal degeneration, while skeletal deformities occur in the appendicular skeleton and include short‐limbed dwarfism with elbow and hip dysplasia . The disease inheritance is autosomal recessive and was recently linked to a mutation in COL9A2 and COL9A3 genes …”