EFNB3 Frameshift Variant in Weimaraner Dogs with a Condition Resembling a Congenital Mirror Movement Disorder.

backgroundCongenital mirror movement disorders (CMMs) are clinically and genetically heterogeneous in human patients. CMMs have not been documented to occur spontaneously in animals.

objectiveThe objective of this work was to document the first case of CMMs spontaneously occurring in Weimaraner dogs and to identify the underlying genetic cause.

methodsClinical and pathological investigations were performed. Genetic investigations used linkage and autozygosity mapping followed by whole-genome sequencing of 3 affected dogs and 1489 control dogs to identify disease-associated variants.

resultsThree of 11 puppies in a litter of Weimaraner dogs exhibited an abnormal gait characterized by synchronized saltatorial locomotion. Their phenotype was tentatively termed congenital mirror movement disorder 1 (CMM1). The underlying genetic cause was identified as a 2-bp duplication in EFNB3 encoding ephrin-B3, a transmembrane protein important for axon guidance and spinal midline barrier formation during neurodevelopment. The identified variant, XM_038536724.1:c.643_644dup, is predicted to lead to a frameshift and introduction of a premature stop codon XP_038392652.1:p.(Ala216Valfs*79). CMM1 is inherited as an autosomal recessive trait in these dogs.

conclusionsSimilar to humans, CMMs may occur in dogs as an inherited disease as a result of a spontaneously arisen genetic variant. The CMM1 phenotype in dogs resembles the phenotype of experimentally induced Efnb3