Was the gene identified?

Genomic analyses in Cavalier King Charles spaniels identify loci associated with clinical signs of Chiari-like malformation and Syringomyelia

Courtney R Sparks 1, Jonah N Cullen 2, Michael W Vandewege 1, Meghan Leber 1, Katie M Minor 2, Steven G Friedenberg 2, Natasha J Olby 3 4

Background
Chiari-like malformation and syringomyelia (CMSM) are highly prevalent in Cavalier King Charles Spaniels (CKCS), manifesting as neuropathic pain and scratching behaviors. Despite the frequent use of MRI for diagnosis, there is a poor correlation between imaging findings and clinical signs. Prior genetic studies have focused on morphologic traits such as skull shape, but this study aimed to identify genetic loci associated directly with the clinical signs of pain and scratching. The hypothesis was that mapping clinical phenotypes rather than imaging abnormalities would reveal novel genetic associations.

Methods
A total of 174 CKCS underwent genotyping using the Axiom K9 HD SNP array. MRI scans were reviewed to determine the presence of syringomyelia (SM), and owner-completed questionnaires assessed clinical signs using the Chiari-like Malformation Pain and Scratch Tool (ChiMPS-T). Four genome-wide association studies (GWAS) were conducted: two using case-control models (SM and clinical signs), and two using quantitative traits (total pain score [TPS] and total scratch score [TSS]). Whole genome sequencing (WGS) of 21 CKCS and 501 control dogs was used to identify segregating variants in loci of interest.

Results
No genomic regions were significantly associated with SM. However, a locus on chromosome CFA26, near the ZWINT gene, showed suggestive association with clinical signs and replicated previous findings based on skull morphometry. Quantitative GWAS identified loci on CFA2 and CFA38 associated with scratching (TSS) and a distinct locus on CFA13 (involving the KCTD8 gene) associated with pain (TPS). Two ZWINT missense variants were identified that segregated with clinical phenotype, though they were also found in other breeds. A predicted 2.5 kb tandem duplication downstream of ZWINT, initially associated with clinical phenotype, was later disproven via long-read sequencing.

Limitations
The retrospective inclusion of some dogs, incomplete phenotype data (particularly for early study enrollees), and variable age at MRI acquisition may have introduced misclassification or reduced power. Small sample sizes, particularly for WGS, and reliance on owner-reported signs also limit generalizability. Additionally, some potentially significant variants could not be fully analyzed due to high rates of missing genotype data.

Conclusions
The study identified several loci associated with clinical signs in CKCS with CMSM, supporting a polygenic basis for the condition. The CFA26 locus near ZWINT emerged as a consistent region of interest across studies using both morphometric and clinical phenotypes. The findings highlight the value of using clinical signs rather than morphological traits alone for phenotype definition in genetic studies of CMSM. Further work is needed to validate candidate variants and to explore regulatory variants and gene expression differences underlying disease manifestation.

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