In other species: crab-eating macaque , domestic cat , horse , pig , taurine cattle , sheep

Categories: Haematopoietic system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 306700 (trait) , 300841 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0010602: hemophilia A

Mendelian trait/disorder: yes

Mode of inheritance: X-linked recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2002

Cross-species summary: Also called factor VIII deficiency. Impaired coagulability of the blood, with a consequential strong tendency to bleed, due to a deficiency of clotting factor VIII. Since the gene for this factor is located on the X chromosome, the disorder is expected to be X-linked. As with haemophilia B, this expectation has been confirmed in all species of mammal in which the disorder has been reported. In humans, there are hundreds of different mutations that give rise to haemophilia A. In domesticated animals, the disorder has been reported in a large range of species.

Species-specific name: classical haemophilia/hemophilia

Species-specific description: The historical section of this entry is based on information in the review by Lozier and Nichols (2013). Some missing references were also gleaned from this review. FN is grateful to the authors for their very useful review.

History: A colonly of Irish Setters in which this disorder segregates was established in 1947 at the University of North Carolina at Chapel Hill, by Kenneth M. Brinkhous. It was first described by Graham et al. (1949) and Brinkhous and Graham (1950). A Miniature Schnauzer colony was established at Queens University, Toronto, in 1980 (Giles et al., 1982).

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), a likely causal mutation in the canine factor 8 gene (F8) was discovered: in the Queens University Miniature Schnauzer colony, an intronic inversion that results in "aberrant splicing and premature termination of transcription of the FVIII gene, resulting in a polyadenylated transcript lacking exons distal to 22 and terminating with a novel sequence element (NSE)" (Hough et al., 2002); and (a few months later) in the Chapel Hill Irish Setter colony, the same intron-22 inversion (Lozier et al., 2002). This inversion is very similar to a causal mutation in the human F8 gene. In an affected male German Shepherd dog, Mischke et al. (2011) reported a nonsense mutation in the F8 gene, namely a "single-base exchange at nucleotide position 98 (TGG>TAG) was detected resulting in a STOP codon (Trp33Stop) in frame". Two additional causal mutations were reported by Christopherson et al. (2014): c.1412C>G, P471R in exon 10 in a Boxer, and c.1643G>A, p.C548Y in exon 11 in a German Shepherd dog. Lozier et al. (2016) reported a male Old English Sheep Dog with severe haemophilia A, apparently due to a novel variant, namely "a C→T transition in exon 12 of the factor VIII gene [c.1786C>T] that created a premature stop codon at amino acid 577 in the A2 domain of the protein [p.Arg577Stop] . . . [which] is analogous to the previously described human factor VIII mutation at Arg583, which likewise is a CpG dinucleotide transition causing a premature stop codon in exon 12". Kehl et al. (2021) reported "a short interspersed nuclear element (SINE) insertion in exon 14 of the F8 gene" as the likely causal variant in two affected "related male Rhodesian Ridgebacks". Hytönen et al. (2023) investigated "hemophilia A in two distinct Labrador Retriever (LR) pedigrees. Whole-genome sequencing on an affected dog from litter 1 identified a case-specific frameshift deletion variant in F8 predicted to cause a premature stop codon (c.2923_2924del, p.(E975Kfs*8)). This variant was hemizygous in all the affected males from litter 1 (n = 3), while all the unaffected LRs in the pedigree were heterozygous or wild-type (n = 22). Additionally, screened samples from 199 LRs were all found to be wild-type. ... However, it is important to note that the affected LR with decreased FVIII activity from litter 2 was wild-type for the identified deletion variant, and no segregating F8 variants were detected when this dog's DNA sample was whole-genome sequenced." After diagnosing factor VIII deficiency in a Border Collie male pup whose two litter-brothers had been euthanased due to "acute hematoma formation", and subsequently sequencing the F8 genes in the surviving pup and its dam, Brockmann et al. (2023) discovered "a deletion in exon 14 of the F8 gene. This c.3206delA variant leads to a frameshift in amino acid sequence and a premature stop codon (p.Asn1069IlefsTer7). The detection of the mutation and consequent testing of related dogs revealed that the deletion most likely had occurred spontaneously in the mother and had been transmitted to several of her offspring in different litters."

Clinical features: Dogs with haemophilia A present with spontaneous bleeding, including bleeding in soft tissue, joints (causing lameness) and body cavities. Excessive bleeding is reported after tooth extraction or after deciduous teeth are lost and after surgery (Mischke et al., 1996; Nichols et al., 2010). Coagulation analysis will show a markedly prolonged activated partial thromboplastin time (APTT) with a low factor VIII activity (Gavazza et al., 2014; Nishitani and Kitoh, 2021). Severity of clinical presentation varies between breeds. IT thanks DVM student Yi Fei Choong, who provided the basis of this contribution in May 2023.

Breeds: Belgian Shepherd Dog, Malinois (Dog) (VBO_0200147), Border Collie (Dog) (VBO_0200193), Boxer (Dog) (VBO_0200210), Cocker Spaniel (Dog) (VBO_0200372), German Shepherd Dog (Dog) (VBO_0200577), German Shorthaired Pointer (Dog) (VBO_0200583), Golden Retriever (Dog) (VBO_0200610), Irish Setter (Dog) (VBO_0200702), Labrador Retriever (Dog) (VBO_0200800), Miniature Schnauzer (Dog) (VBO_0200896), Old English Sheepdog (Dog) (VBO_0200969), Poodle (Dog) (VBO_0201048), Rhodesian Ridgeback (Dog) (VBO_0201135), Siberian Husky (Dog) (VBO_0201233), Weimaraner (Dog) (VBO_0201401).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: