A LINE-1 insertion situated in the promoter of IMPG2 is associated with autosomal recessive progressive retinal atrophy in Lhasa Apso dogs.. WGS of Lhasa Apso (LA) dog affected with Progressive Retinal Atrophy (PRA)

Canine progressive retinal atrophies (PRAs) are a group of hereditary retinal degenerations in dogs characterised by depletion of photoreceptor cells in the retina which ultimately leads to blindness. PRA in the Lhasa Apso (LA) dog has not previously been clinically characterised or described in the literature, but owners in the UK are advised to have their dog examined through the British Veterinary Association/ Kennel Club/ International Sheep Dog Society (BVA/KC/ISDS) eye scheme annually, and similar schemes that are? in operation in other countries. After the exclusion of 26 previously reported canine retinal mutations in LA PRA-affected dogs, we sought to identify the genetic cause of PRA in this breed. Results: Analysis of whole-exome sequencing data of three PRA-affected LA and three LA without signs of PRA did not identify any exonic or splice site variants, suggesting the causal variant was non-exonic. We subsequently undertook a genome-wide association study (GWAS), which identified a 1.3 Mb disease-associated region on canine chromosome 33, followed by whole-genome sequencing analysis that revealed a long interspersed element-1 (LINE-1) insertion upstream of the IMPG2 gene. IMPG2 has previously been implicated in human retinal disease; however, formerly no canine PRAs have been associated with this gene. The identification of this PRA-associated variant has enabled the development of a commercial DNA test for this form of PRA in the breed, termed PRA4, which has been used to determine the genotypes of over 900 LA dogs. A DNA tested group of dogs was used to estimate the allele frequency in the current population. Conclusions: Through the use of GWAS and subsequent sequencing of a PRA case, we have identified a LINE-1 insertion in the retinal candidate gene IMPG2 that is associated with a form of PRA in the LA dog which we have termed ‘PRA4’. Validation of this variant in 447 dogs of 122 breeds found it was private to LA dogs. We envisage the developed DNA test will continue to be utilised to prevent any PRA4 affected dogs being born and to eventually eradicate this form of PRA from the breed.