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BMC Genet. 2018 Mar 22;19(1):16. doi: 10.1186/s12863-018-0605-z.

A genome-wide association study identifies candidate loci associated to syringomyelia secondary to Chiari-like malformation in Cavalier King Charles Spaniels.

Author information

Department of Neurosciences, CHU Sainte Justine Research Center, University of Montréal, 3175 Cote-Sainte-Catherine, Room 3.17.006, Montreal, QC, H3T 1C5, Canada.
School of Veterinary Medicine, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7AL, UK.
Department of Medical Imaging, London Health Sciences Centre, London, ON, N6A 5A5, Canada.
Stone Lion Veterinary Hospital, 42 High Street, Wimbledon, SW19 5AU, UK.
Dick White Referrals, Six Mile Bottom, Cambridgeshire, CB8 0UH, UK.
Thames Valley Veterinary Services, London, ON, N6A 4V2, Canada.
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, 3584, CM, The Netherlands.
Montreal Neurological Institute and McGill University, Montreal, QC, H3A 2B4, Canada.
Fitzpatrick Referrals, Godalming, Surrey, GU7 2QQ, UK.
Department of Neurosciences, CHU Sainte Justine Research Center, University of Montréal, 3175 Cote-Sainte-Catherine, Room 3.17.006, Montreal, QC, H3T 1C5, Canada.



Syringomyelia (SM) is a common condition affecting brachycephalic toy breed dogs and is characterized by the development of fluid-filled cavities within the spinal cord. It is often concurrent with a complex developmental malformation of the skull and craniocervical vertebrae called Chiari-like malformation (CM) characterized by a conformational change and overcrowding of the brain and cervical spinal cord particularly at the craniocervical junction. CM and SM have a polygenic mode of inheritance with variable penetrance.


We identified six cranial T1-weighted sagittal MRI measurements that were associated to maximum transverse diameter of the syrinx cavity. Increased syrinx transverse diameter has been correlated previously with increased likelihood of behavioral signs of pain. We next conducted a whole genome association study of these traits in 65 Cavalier King Charles Spaniel (CKCS) dogs (33 controls, 32 with extreme phenotypes). Two loci on CFA22 and CFA26 were found to be significantly associated to two traits associated with a reduced volume and altered orientation of the caudal cranial fossa. Their reconstructed haplotypes defined two associated regions that harbor only two genes: PCDH17 on CFA22 and ZWINT on CFA26. PCDH17 codes for a cell adhesion molecule expressed specifically in the brain and spinal cord. ZWINT plays a role in chromosome segregation and its expression is increased with the onset of neuropathic pain. Targeted genomic sequencing of these regions identified respectively 37 and 339 SNPs with significantly associated P values. Genotyping of tagSNPs selected from these 2 candidate loci in an extended cohort of 461 CKCS (187 unaffected, 274 SM affected) identified 2 SNPs on CFA22 that were significantly associated to SM strengthening the candidacy of this locus in SM development.


We identified 2 loci on CFA22 and CFA26 that contained only 2 genes, PCDH17 and ZWINT, significantly associated to two traits associated with syrinx transverse diameter. The locus on CFA22 was significantly associated to SM secondary to CM in the CKCS dog breed strengthening its candidacy for this disease. This study will provide an entry point for identification of the genetic factors predisposing to this condition and its underlying pathogenic mechanisms.


CKCS dog breed; Chiari malformation; Cranial MRI measurements; Syringomyelia; Whole genome association study

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