Validation of a Chromosome 14 Risk Haplotype for Idiopathic Epilepsy in the Belgian Shepherd Dog Found to Be Associated with an Insertion in the RAPGEF5 Gene

Genes (Basel). 2022 Jun 23;13(7):1124. doi: 10.3390/genes13071124.


An idiopathic epilepsy (IE) risk haplotype on canine chromosome (CFA) 14 has been reported to interact with the CFA37 common risk haplotype in the Belgian shepherd (BS). Additional IE cases and control dogs were genotyped for the risk haplotypes to validate these previous findings. In the new cohort, the interaction between the two regions significantly elevated IE risk. When the haplotypes were analyzed individually, particular haplotypes on both CFA14 (ACTG) and 37 (GG) were associated with elevated IE risk, though only the CFA37 AA was significantly associated (p < 0.003) with reduced risk in the new cohort. However, the CFA14 ACTG risk was statistically significant when the new and previous cohort data were combined. The frequency of the ACTG haplotype was four-fold higher in BS dogs than in other breeds. Whole genome sequence analysis revealed that a 3-base pair predicted disruptive insertion in the RAPGEF5 gene, which is adjacent to the CFA14 risk haplotype. RAPGEF5 is involved in the Wnt-β-catenin signaling pathway that is crucial for normal brain function. Although this risk variant does not fully predict the likelihood of a BS developing IE, the association with a variant in a candidate gene may provide insight into the genetic control of canine IE.

Keywords: RAPGEF5; dog; idiopathic epilepsy; risk haplotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Belgium
  • Dog Diseases* / genetics
  • Dogs
  • Epilepsy* / genetics
  • Epilepsy* / veterinary
  • Genetic Predisposition to Disease
  • Haplotypes
  • Humans
  • ras Guanine Nucleotide Exchange Factors / genetics


  • RAPGEF5 protein, human
  • ras Guanine Nucleotide Exchange Factors

Grants and funding

Samples and financial support for this work were obtained under Morris Animal Foundation Grants (D05CA-072, DO2CA-62), American Kennel Club Canine Health Foundation Grants (#1613, 2015, 2614, 02936), the Jane and Aatos Erkko Foundation, the Academy of Finland, the Dog Health Research Fund, the Helsinki Institute of Life Science, and Wisdom Health, and a grant from Dutch Belgian Shepherd Breeding associations NVBH and BHCN.