A Splice Acceptor Variant inIs Associated with Spondylocostal Dysostosis in a Litter of Mixed-Breed Dogs.

Abstract

BACKGROUND/OBJECTIVES: Spondylocostal dysostosis (SCDO) is a rare disorder characterized by congenital malformations of the spine and ribs. SCDO affects 1 in 40,000 human births, with rare cases also reported in dogs. Mutations in, encoding a critical Notch signaling pathway ligand, account for a majority of human SCDO cases. The remaining cases have variants in,,,,and, which code for proteins in the Notch pathway. A mixed-breed litter of three dogs presented with varying degrees of spinal malformations and underwent comprehensive phenotyping including radiographic and neurologic examination. Two littermates demonstrated classic SCDO features including shortened torsos, vertebral malformations, and rib abnormalities, while a third showed only caudal vertebral truncation. METHODS: Short-read whole-genome sequencing was performed on all three animals, followed by variant filtering and analysis using the two severely affected dogs as cases and 173 control dogs of various breeds. Variants were prioritized based on segregation patterns, population frequency, and predicted functional impact using established bioinformatics tools. RESULTS: Variant analysis identified a novel splice acceptor variant in(c.650-2A>C). This mutation, located at the splice acceptor site preceding exon 5, is predicted to disrupt critical EGF-like domains and O-fucosylation sites essential forprotein function. CONCLUSIONS: This study identifies a DLL3 splice variant causing SCDO in dogs, demonstrating phenotypic conservation with humans. These findings refine our understanding of genotype-phenotype correlations and demonstrate the value of comparative genomics for rare developmental disorders.