A missense variant in IFT122 associated with a canine model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a blinding eye disease affecting nearly two million people worldwide. Dogs are affected with a similar illness termed progressive retinal atrophy (PRA). Lapponian herders (LHs) are affected with several types of inherited retinal dystrophies, and variants in PRCD and BEST1 genes have been associated with generalized PRA and canine multifocal retinopathy 3 (cmr3), respectively. However, all retinal dystrophy cases in LHs are not explained by these variants, indicating additional genetic causes of disease in the breed. We collected DNA samples from 10 PRA affected LHs, with known PRCD and BEST1 variants excluded, and 34 unaffected LHs. A genome-wide association study identified a locus on CFA20 (praw = 2.4 × 10-7, pBonf = 0.035), and subsequent whole-genome sequencing of an affected LH revealed a missense variant, c.3176G>A, in the intraflagellar transport 122 (IFT122) gene. The variant was also found in Finnish Lapphunds, in which its clinical relevancy needs to be studied further. The variant interrupts a highly conserved residue, p.(R1059H), in IFT122 and likely impairs its function. Variants in IFT122 have not been associated with retinal degeneration in mammals, but the loss of ift122 in zebrafish larvae impaired opsin transport and resulted in progressive photoreceptor degeneration. Our study establishes a new spontaneous dog model to study the role of IFT122 in RP biology, while the affected breed will benefit from a genetic test for a recessive condition.

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.

Multiocular defect has been described in different canine breeds, including the Old English Sheepdog. Affected dogs typically present with multiple and various ocular abnormalities. We carried out whole genome sequencing 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 affected by multiocular defect and three control dogs without evidence of inherited eye disease). Only one of the twenty-two variants segregated correctly with multiocular defect. 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 Old English Sheepdogs affected by multiocular defect 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. In humans, variants in the COL11A1 gene are associated with Stickler syndrome type II, also dominantly inherited.

A Missense Variant in the Bardet-Biedl Syndrome 2 Gene (BBS2) Leads to a Novel Syndromic Retinal Degeneration in the Shetland Sheepdog.

Canine progressive retinal atrophy (PRA) describes a group of hereditary diseases characterized by photoreceptor cell death in the retina, leading to visual impairment. Despite the identification of multiple PRA-causing variants, extensive heterogeneity of PRA is observed across and within dog breeds, with many still genetically unsolved. This study sought to elucidate the causal variant for a distinct form of PRA in the Shetland sheepdog, using a whole-genome sequencing approach. Filtering variants from a single PRA-affected Shetland sheepdog genome compared to 176 genomes of other breeds identified a single nucleotide variant in exon 11 of the Bardet-Biedl syndrome-2 gene (BBS2) (c.1222G>C; p.Ala408Pro). Genotyping 1386 canids of 155 dog breeds, 15 cross breeds and 8 wolves indicated the c.1222G>C variant was only segregated within Shetland sheepdogs. Out of 505 Shetland sheepdogs, seven were homozygous for the variant. Clinical history and photographs for three homozygotes indicated the presence of a novel phenotype. In addition to PRA, additional clinical features in homozygous dogs support the discovery of a novel syndromic PRA in the breed. The development and utilization of a diagnostic DNA test aim to prevent the mutation from becoming more prevalent in the breed.