A missense variant (c.1645G > A) in feline F8 is associated with severe factor VIII deficiency in cats with hemophilia A

Background Hemophilia A is inherited as an X-linked recessive bleeding disorder that typically manifests in males. The trait is caused by deficiency or dysfunction of coagulation factor VIII (FVIII). Although hemophilia A has been identified in cats, genetic analyses are limited to description of a non-coding variant in the FVIII gene ( F8) in a single affected male. The current study describes the discovery of hemophilia A in both male and female domestic cats and the identification of an F8 coding sequence variant associated with severe FVIII deficiency. Results A total of 19 cats from a single household underwent coagulation testing, with 7 cats diagnosed with hemophilia A based on FVIII coagulant activity (FVIII: C) below 10%. The affected cats ( n = 4 male, 3 female) had severe FVIII: C deficiency, with a median value of 3%, and significantly prolonged activated partial thromboplastin time compared with unaffected cats. Clinical signs of hemophilia included bleeding at injection sites and hematoma formation. Sequencing of all F8 coding exons and exon-intron junctions of affected cats identified a single missense variant in exon 11, c.1645G > A, predicted to cause an amino acid substitution from aspartic acid to asparagine at FVIII position 549. All genotyped affected male cats were hemizygous and an affected female was homozygous for the variant. Unaffected cats were either hemizygous or homozygous wild-type or female heterozygotes. No additional F8 coding variants were identified in affected cats, and the previously reported feline non-coding variant was absent. Conclusions These findings indicate that hemophilia A should be included in the differential for both male and female cats with signs of abnormal bleeding. A sequence variant in F8 exon 11, previously identified in human hemophilia A, was found exclusively in the affected cats in this population. This is the first report of a coding sequence variant in feline F8 associated with severe hemophilia A, found in a household of domestic shorthair cats.