A genome-wide association study identifiescandidate loci associated to syringomyeliasecondary to Chiari-like malformation inCavalier King Charles Spaniels
2018
Background: 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. Results: 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. Conclusions: 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.
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