Deletion in CACNA1F gene causes X-linked progressive retinal atrophy in English Cocker Spaniel dogs

Abstract Background Progressive retinal atrophy (PRA) was diagnosed in four related male English Cocker Spaniels (ECS) between the ages of 3 and 4 years. All affected dogs were born to clinically unaffected parents that had tested negative for known PRA-causing variants through commercial vendors. Pedigree analysis revealed that the mothers of the affected dogs were paternal half-siblings, and their father had been reported as visually impaired, suggesting an X-linked recessive mode of inheritance. Results To identify the underlying genetic cause, we performed homozygosity mapping, identifying six candidate regions, and whole-genome sequencing. A single high-impact coding variant—a 1-bp deletion in exon 36 of the CACNA1F gene on X chromosome (UU_Cfam_GSD_1.0 NC_049260.1 g.42,516,353del) —was identified. This variant is predicted to cause a frameshift and premature stop codon (XM_038587436.1, c.4,481del, XP_038443364.1:Phe1482LeufsTer8) and was found in a hemizygous state in all affected males and heterozygous in their mothers, while being absent in fathers as well as unaffected control dogs. A specifically designed PCR test was developed and applied to a broader cohort of 92 related and unrelated ECS dogs, confirming the segregation of this variant. Conclusions This study identified a novel segregating CACNA1F variant, likely to be responsible for an X-linked recessive form of PRA in the ECS. Given that CACNA1F is already associated with retinal disorders in other mammals, including humans, this finding adds to its relevance across species. This study highlights the importance for breeders of regular health examinations for late-onset conditions and prompt reporting of hereditary disorders of unknown cause to enable rapid identification of their genetic basis. Development and implementation of specific genetic screening tests are recommended to assess the frequency of this variant in ECS and other populations, inform breeding strategies, and prevent further dissemination of this deleterious variant.