Identification of a Novel Idiopathic Epilepsy Risk Locus and a Variant in the CCDC85A Gene in the Dutch Partridge Dog

SIMPLE SUMMARY: A significant percentage of Dutch partridge dogs suffers from epileptic seizures. Previous studies indicated that this is likely the result of genetic idiopathic epilepsy, but to date, little to no knowledge exists on the genetic cause. This study aimed to identify (a) causal variant(s) and/or risk loci associated with the disease. A risk locus for idiopathic epilepsy was described for the first time on chromosome 12. Furthermore, a variant in the CCDC85A gene was found to increase the risk of disease in homozygous variant dogs. Further research should be conducted to determine whether the chromosome 12 risk locus and CCDC85A variant can be used in breeding decisions. ABSTRACT: (1) Idiopathic epilepsy (IE) is thought to have a genetic cause in several dog breeds. However, only two causal variants have been identified to date, and few risk loci are known. No genetic studies have been conducted on IE in the Dutch partridge dog (DPD), and little has been reported on the epileptic phenotype in this breed. (2) Owner-filled questionnaires and diagnostic investigations were used to characterize IE in the DPD. A genome-wide association study (GWAS) involving 16 cases and 43 controls was performed, followed by sequencing of the coding sequence and splice site regions of a candidate gene within the associated region. Subsequent whole-exome sequencing (WES) of one family (including one IE-affected dog, both parents, and an IE-free sibling) was performed. (3) IE in the DPD has a broad range in terms of age at onset, frequency, and duration of epileptic seizures. Most dogs showed focal epileptic seizures evolving into generalized seizures. A new risk locus on chromosome 12 (BICF2G630119560; p(raw) = 4.4 × 10(−7); p(adj) = 0.043) was identified through GWAS. Sequencing of the GRIK2 candidate gene revealed no variants of interest. No WES variants were located within the associated GWAS region. However, a variant in CCDC85A (chromosome 10; XM_038680630.1: c.689C > T) was discovered, and dogs homozygous for the variant (T/T) had an increased risk of developing IE (OR: 6.0; 95% CI: 1.6–22.6). This variant was identified as likely pathogenic according to ACMG guidelines. (4) Further research is necessary before the risk locus or CCDC85A variant can be used for breeding decisions.