A genome-wide association study identifies candidate loci associated to syringomyelia secondary to Chiari-like malformation in Cavalier King Charles Spaniels
2018
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
overcrowdingof 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 diameterof the syrinx cavity. Increased syrinx
transverse diameterhas 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
ZWINTon CFA26. PCDH17 codes for a cell adhesion molecule expressed specifically in the brain and spinal cord.
ZWINTplays a role in
chromosome segregationand 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
candidacyof 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 breedstrengthening its
candidacyfor 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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