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

Abstract

BACKGROUND Congenital mirror movement disorders (CMMs) are clinically and genetically heterogeneous in human patients. CMMs have not been documented to occur spontaneously in animals. OBJECTIVE The objective of this work was to document the first case of CMMs spontaneously occurring in Weimaraner dogs and to identify the underlying genetic cause. METHODS Clinical 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. RESULTS Three 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. CONCLUSIONS Similar 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-/- knockout mice. So far, no human patients with EFNB3-related CMMs have been reported. Our study provides the first naturally occurring large-animal model for CMMs. EFNB3 should be considered a candidate gene in human CMM patients with unclear disease etiology. © 2025 International Parkinson and Movement Disorder Society.