A frameshift-deletion mutation in Reelin causes cerebellar hypoplasia in White Swiss Shepherd dogs.

Littlejohn, Mathew D; Sneddon, Nick; Dittmer, Keren; Keehan, Mike; Stephen, Melissa; Drögemüller, Michaela; Garrick, Dorian (2023). A frameshift-deletion mutation in Reelin causes cerebellar hypoplasia in White Swiss Shepherd dogs. Animal genetics, 54(5), pp. 632-636. Wiley 10.1111/age.13336

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Cerebellar hypoplasia is a heterogeneous neurological condition in which the cerebellum is smaller than usual or not completely developed. The condition can have genetic origins, with Mendelian-effect mutations described in several mammalian species. Here, we describe a genetic investigation of cerebellar hypoplasia in White Swiss Shepherd dogs, where two affected puppies were identified from a litter with a recent common ancestor on both sides of their pedigree. Whole genome sequencing was conducted for 10 dogs in this family, and filtering of these data based on a recessive transmission hypothesis highlighted five protein-altering candidate variants - including a frameshift-deletion of the Reelin (RELN) gene (p.Val947*). Given the status of RELN as a gene responsible for cerebellar hypoplasia in humans, sheep and mice, these data strongly suggest the loss-of-function variant as underlying these effects. This variant has not been found in other dog breeds nor in a cohort of European White Swiss Shepherds, suggesting a recent mutation event. This finding will support the genotyping of a more diverse sample of dogs, and should aid future management of the harmful allele through optimised mating schemes.

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