Abstract
BackgroundIdiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date. The seizure characteristics, including focal and generalised seizures, are similar between the two species, with gene discovery facilitated by the reduced genetic heterogeneity of purebred dogs. We have recently identified a risk locus for idiopathic epilepsy in the Belgian Shepherd breed on a 4.4 megabase region on CFA37.ResultsWe have expanded a previous study replicating the association with a combined analysis of 157 cases and 179 controls in three additional breeds: Schipperke, Finnish Spitz and Beagle (pc = 2.9e–07, pGWAS = 1.74E-02). A targeted resequencing of the 4.4 megabase region in twelve Belgian Shepherd cases and twelve controls with opposite haplotypes identified 37 case-specific variants within the ADAM23 gene. Twenty-seven variants were validated in 285 cases and 355 controls from four breeds, resulting in a strong replication of the ADAM23 locus (praw = 2.76e–15) and the identification of a common 28 kb-risk haplotype in all four breeds. Risk haplotype was present in frequencies of 0.49–0.7 in the breeds, suggesting that ADAM23 is a low penetrance risk gene for canine epilepsy.ConclusionsThese results implicate ADAM23 in common canine idiopathic epilepsy, although the causative variant remains yet to be identified. ADAM23 plays a role in synaptic transmission and interacts with known epilepsy genes, LGI1 and LGI2, and should be considered as a candidate gene for human epilepsies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1651-9) contains supplementary material, which is available to authorized users.
Highlights
Idiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date
Epilepsy phenotypes The seizure characteristics of idiopathic epilepsy in the studied breeds were described based on the detailed epilepsy questionnaire collected from the epileptic dogs in each breed
No evidence for sex predisposition was found in Belgian Shepherds or Schipperkes, but more affected males are reported in Beagles [17] and Finnish Spitz [16]
Summary
Idiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date. The seizure characteristics, including focal and generalised seizures, are similar between the two species, with gene discovery facilitated by the reduced genetic heterogeneity of purebred dogs. We have recently identified a risk locus for idiopathic epilepsy in the Belgian Shepherd breed on a 4.4 megabase region on CFA37. Epilepsy is a common neurological disease in both human and dog. The cause may be directly genetic or idiopathic (IE) [1]. Many human forms of epilepsy are considered to have a genetic basis though little is known about the underlying risk genes and variants for common forms of epilepsy despite increasingly powerful methodologies [3]. Rare Mendelian forms of the human disease have been associated with many ion channel subunits, other types of gene pathways, related to neurodevelopment, mitochondria, and other cellular processes, are being identified [3]
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