Identification of a Novel Mutation in the SERPINE1 Gene Causing Clinical Hyperfibrinolysis in English Springer Spaniel Dogs

ABSTRACT Background A 7‐month‐old female spayed English Springer Spaniel (ESS) was evaluated for spontaneous hemoperitoneum. Hyperfibrinolysis was identified on thromboelastography. Hypothesis/Objectives To identify a genetic mutation causing congenital hyperfibrinolysis in the proband and evaluate the prevalence of the mutation in the ESS breed. Animals Client‐owned ESS with hemorrhage and a non‐affected littermate. Samples of DNA from 3 ESS, 1 Welsh Springer Spaniel (WSS) with unexplained hemorrhage, and 199 ESS with no history of hemorrhage. Methods Whole genome sequencing (WGS) of the proband with variant filtering against an in‐house WGS database of 671 presumably unaffected dogs identified a deleterious variant of SERPINE1 unique to the proband, which encodes for plasminogen activator inhibitor 1 (PAI‐1). SERPINE1 was genotyped in the remaining animal population by Sanger sequencing or a Taqman assay. Liquid chromatography tandem mass spectrometry (LC–MS/MS) was performed on platelet pellets from the proband, a littermate, and three unrelated healthy ESS. Results Whole genome sequencing of the proband identified a unique homozygous insertion at chr6:8640592 in exon 1 of SERPINE1, which is predicted to cause a premature stop codon. The unaffected littermate was heterozygous for the mutation. Two unrelated ESS and 1 WSS with post‐operative hemorrhage were homozygous for the mutation. Absence of PAI‐1 in the proband's platelets was documented using LC–MS/MS. Conclusions and Clinical Importance This novel mutation in SERPINE1 is associated with the absence of the PAI‐1 protein in platelets and might cause hemorrhage because of hyperfibrinolysis in ESS and related breeds.