Update on Chiari Malformation / Syringomyelia genetic research
Clare Rusbridge
European and RCVS Specialist in Veterinary Neurology

Identification of the genes responsible for Chiari malformation (CM) with or without syringomyelia (SM) will help better understand the underlying pathogenic mechanisms for better diagnosis, prognosis and clinical management of this devastating condition. These studies will also help unravel some of the complexity involved in this malformation and in the embryonic development of the affected structures. We have constructed a geneology of more than 10000 related Cavalier King Charles Spaniel (CKCS) dogs spanning 24 generations across 3 continents ( North America, Australia and Europe) and established a wide DNA collection of over 1000 samples from mainly the CKCS breed but including samples from 6 other breeds affected with CM/SM of various degrees of genetic relatedness to the CKCS (King Charles Cavalier Spaniels, Yorkshire Terrier, Bull Terrier, Boston Terrier, Brussels Griffon, Chihuahua).

SM is present in at least 50% if CKCS affected with CM making whole genome association and linkage-based studies feasible within this breed. Due to the complex inbreeding in the CKCS, a preliminary genetic analysis was necessary to evaluate the informativeness of the genetic markers and hence the feasibility of a whole genome scan in such breed.

Consequently, 10 dogs were selected for genotyping with 122 markers distributed among the 38 autosomes and X chromosome. Next and with the support of the Marshfield genotyping services from NIH, we have recently completed the genotyping of 173 CKCS dogs over 249 microsatellite markers distributed over the 28 autosomes and the X chromosome.

The dogs are distributed over 34 dog pedigrees including multiple affected and unaffected sibs and half sibs with parents. We are currently in the process of analysing the data for linkage.

Founder events and stringent breeding practices have made the CKCS breed as all the other purebred dogs, a closed genetic pool. As a result, linkage disequilibrium (LD) analysis is a promising strategy for gene mapping studies and we plan to use this strategy to identify genes predisposing to CM/SM. As CM is presenting variable degrees of expression in nearly 100%of the CKCS dogs, this means association studies in this single breed are not feasible and comparison to other breeds is necessary especially since closely related breeds are more likely to share ancestral chromosomes and carry the same disease allele.

We will initially conduct a whole genome scan using dogs from the CKCS breed and other modern and closely-related breeds. We will then use techniques such as allele sharing, homozygosity mapping and association testing to pinpoint a candidate region. We will next try to narrow down and delineate the minimal genetic interval containing the CM gene(s) by LD mapping and haplotype association studies using a dense SNP (single nucleotide polymorphisms) coverage between historically older but related breeds also affected with CM/SM.

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