A CACNA2D2-Related Recessive Form of Cerebellar Abiotrophy in Angus Cattle.

Abstract

Cerebellar disease in ruminants is often virus-induced and non-genetic, but there are also rare inherited forms of cerebellar hypoplasia and cerebellar abiotrophy (CA). So far, no causal variant has been reported for these conditions in cattle. Two inbred Angus calves suspected of having cerebellar disease were reported in Scotland. The aims of this study were to characterize the clinicopathological phenotype of Angus calves affected by a cerebellar disease, to identify a causal variant assuming autosomal monogenic recessive inheritance and to evaluate its prevalence in Angus populations. Clinicopathological investigations were performed, including the exclusion of prevalent teratogenic viruses as well as a multiple-case whole-genome sequencing (WGS) approach. The two affected Angus calves showed congenital intention tremor and brain examination detected cerebellar abiotrophy. Genetic analysis identified a private homozygous missense variant in the bovine CACNA2D2 gene (XP_024839037.1:p.(Cys395Arg)), which is linked to neurological disorders in other species, including a form of cerebellar atrophy in humans. This variant was classified as pathogenic and shown to be absent in sequence data from over 5000 other cattle with available WGS data as well as in a cohort of 16 purebred Angus cattle from Switzerland. The variant is proposed to cause a rare form of CA in Angus and therefore should be monitored in the Angus global population, as previous similar cases were reported elsewhere. For the first time, we characterized a genetic form of cerebellar disease in cattle, providing the first large animal model for a condition related to the CACNA2D2 gene.