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Canine Mendelian disease record

Hemophilia A (Discovered in the German Shepherd Dog; F8 p.C548Y)

Hemophilia A (Discovered in the German Shepherd Dog; F8 p.C548Y). X-linked recessive. Observed in 1 of 266 breeds tested in the Sniff Atlas, with measured carrier frequencies drawn from 242,665 dogs (Donner 2023). Per-dog phenotype outcome depends on penetrance, modifiers, and environment; the carrier frequencies below describe variant prevalence, not disease incidence.

OMIA identifier
OMIA:000437-9615
X-linked recessive
Source dataset
Sniff Atlas v1.0.1 / DOI
The human connection

A model of human hemophilia A

Dogs with this condition carry a change in F8. In people, changes in the same gene cause hemophilia A. That makes affected dogs a naturally-occurring model of the human disease, and it is part of why studying dogs moves medicine forward for everyone. It does not mean your dog has the human disease. It means the two share an underlying biology.

In people, the disease is described as: The most common form of hemophilia characterized by spontaneous or prolonged hemorrhages due to factor VIII deficiency.

In humans it is also called: HEMA, classic hemophilia, classical hemophilia, congenital factor VIII disorder, factor 8 deficiency.

MONDO:0010602 OMIM 306700

Mapped from OMIA via the human disease's OMIM entry to the Mondo Disease Ontology (Monarch Initiative, CC-BY 4.0). Sniff renders this as a model-of link; the canine disease remains the subject of this page.

About this disease

From OMIA's curated record

Documented in OMIA (Online Mendelian Inheritance in Animals). This describes the disease as recorded in the published literature, not a prediction for any individual dog. As of 2026-06-03.

Summary

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.

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.

Molecular genetics

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."

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).

Human analog

OMIA links this condition to its human counterpart in OMIM (Mendelian Inheritance in Man), the place to read across to the deeper human literature for the same biology.

Disease · OMIM 306700 Gene · OMIM 300841

Source: OMIA (Nicholas, Tammen & the Sydney Informatics Hub), entry OMIA:000437-9615, doi:10.25910/2AMR-PV70 (CC-BY 4.0).

Signs & cross-references

How it presents

Catalogued in the Mondo disease ontology (the cross-species disease identity used by the Monarch Initiative) as hemophilia A (MONDO:0010602).

Phenotype terms: Human Phenotype Ontology + Mammalian Phenotype Ontology; disease terms: Mondo (Monarch Initiative). Cross-references curated by OMIA (doi:10.25910/2AMR-PV70, CC-BY 4.0).

The evidence

Published references

The peer-reviewed papers behind this disease, curated by OMIA. Starred entries are OMIA-designated landmark papers. Showing 6 of 140.

References curated by OMIA (Nicholas, Tammen & the Sydney Informatics Hub), doi:10.25910/2AMR-PV70 (CC-BY 4.0). Full list at the OMIA entry.

Predict a litter

Set each parent's status for Hemophilia A (Discovered in the German Shepherd Dog; F8 p.C548Y) and see the odds for their puppies. Single recessive variant, exact Mendelian math.

Parent A
Parent B
NNClear
NmCarrier
NmCarrier
mmAffected
Clear25%
Carrier50%
Affected25%

These are the genetic odds for one known variant, not a promise: a real litter varies around them, and penetrance or other genes can change whether the condition ever appears. Use it to avoid pairing two carriers and to keep a line healthy, not to engineer a dog. Inheritance mode per OMIA.
Your breed

See what Hemophilia A (Discovered in the German Shepherd Dog; F8 p.C548Y) looks like in your dog's breed.
Carrier frequency by breed

Top 1 well-sampled breeds (n ≥ 50)

Maximum per breed across variants in the Donner 2023 cohort, with . The list below is split into well-sampled breeds (n ≥ 50 tested) and small-sample breeds (n < 50, where the Wilson CI typically spans more than 20 percentage points and frequencies should not be compared directly to the well-sampled entries). Frequencies are population-level, not per-litter or per-line.

0%1%2%
German Shepherd<0.1% · n 15,648
n = 15,648 dogs · Donner et al. 2023 carrier-screening cohort · Sniff Atlas
Each bar is one well-sampled breed; the whisker is its Wilson 95% CI, and fainter bars have wider intervals. Frequencies are population-level, not per-litter. Carrier status for Hemophilia A (Discovered in the German Shepherd Dog; F8 p.C548Y) is measured; phenotype outcome depends on penetrance and modifiers.
▸ Full table with Wilson 95% confidence intervals
Breed Carrier frequency n tested
German Shepherd <0.1% 15,648

265 additional breeds in the Donner 2023 cohort were tested but showed no carriers.

Penetrance

From genotype to phenotype

Carrier status is not the same as disease status. Penetrance is the fraction of at-risk dogs that develop the phenotype. The Donner 2023 S4 table tracks this for 1 variant(s) underlying this disease in the cohort.

At-risk dogs evaluated
2
Phenotype confirmed
2
Penetrance range
not yet quantifiable

Fewer than 20 at-risk dogs evaluated; too few to state a penetrance figure.

Predicted disease relevance at the per-dog level is UNPROVEN. The carrier frequency is measured; phenotype outcome is governed by penetrance, environment, and modifier loci. Consult a veterinarian for clinical interpretation.

How to cite this record

Citations

If you use this record in published work, cite the Sniff Atlas (the published dataset that carries the breed-level carrier frequencies) and the upstream sources:

  • Sniff Atlas v1.0.1 for the per-breed carrier frequencies:

    Gehring, M. (2026). Sniff Atlas v1.0.1. Zenodo. https://doi.org/10.5281/zenodo.20566358. CC-BY 4.0.

  • OMIA for the disease definition, inheritance, and gene assignment:

    Nicholas, F. W., & Tammen, I. (2024). OMIA. Sydney Informatics Hub, The University of Sydney. https://doi.org/10.25910/2AMR-PV70. Entry: OMIA:000437-9615.

  • Donner et al. 2023 for the breed × variant carrier-frequency cohort:

    Donner, J., Freyer, J., Davison, S., Anderson, H., Blades, M., Honkanen, L., et al. (2023). Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs. PLOS Genetics, 19(2), e1010651. https://doi.org/10.1371/journal.pgen.1010651.

Full citation formats (BibTeX, RIS, CITATION.cff) at sniff.world/cite.

Related

Related

Last updated
Sources: Sniff Atlas v1.0.1 · OMIA OMIA:000437-9615 · Donner et al. 2023