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Canine Mendelian disease record

Hemophilia B (Discovered in the Lhasa Apso)

Hemophilia B (Discovered in the Lhasa Apso). X-linked recessive. Observed in 0 of 266 breeds tested in the Sniff Atlas, with measured variant frequencies drawn from 242,665 dogs (Donner 2023). Whether a dog carrying this variant is at risk depends on the disease’s inheritance pattern; outcome also depends on penetrance, modifiers, and environment. The frequencies below describe variant prevalence, not confirmed disease incidence.

OMIA identifier
OMIA:000438-9615
X-linked recessive
Linked gene
F9
Human counterpart
In humans, this gene is F9. OMIM 300746 In people, variants in the F9 gene are classified as pathogenic in ClinVar for 3 expert-reviewed conditions.
Source dataset
Sniff Atlas v1.0.1 / DOI
The human connection

A model of human hemophilia B

Dogs with this condition carry a change in F9. In people, changes in the same gene cause hemophilia B. 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: Hemophilia B is a form of hemophilia characterized by spontaneous or prolonged hemorrhages due to factor IX deficiency.

In humans it is also called: HEMB, Christmas disease, congenital factor IX deficiency, congenital factor IX disorder, factor IX deficiency.

MONDO:0010604 OMIM 306900 Mechanism (DisMech) →

Human mechanism pathograph for Hemophilia B is curated in DisMech (Monarch Initiative), joined by exact Mondo id. That page is about people. It is not a treatment plan for a dog.

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

Also called hemophilia B, factor IX deficiency or Christmas disease. This is one of the two X-linked bleeding disorders, haemophilia A being the other. The fact that these two disorders are X-linked in all species reported to date provides strong support for Ohno's suggestion that the X chromosome has been highly conserved throughout evolution.

Clinical features

Haemophilia B is characterised by frequent and spontaneous bleeding into joints, muscles, and body cavities, such as the chest and abdomen, due to a deficiency in factor IX (FIX, F9) (Nichols et al., 2020). This can eventually lead to arthropathy associated with progressive cartilage damage, chronic pain, lameness, and eventually joint destruction (Nichols et al., 2020). Prolonged bleeding from minor wounds and haemorrhagic complications post-surgery may also be observed (Nichols et al., 2010). Disease can be classified into mild, moderate, or severe based on plasma FIX levels with 60-70% of patients having a moderate or severe form (Nichols et al., 2020). Animals with the severe form (<1% coagulation activity) can have bleeding episodes that are life threatening. Most carriers have a reduced FIX activity of 40-60% but do not exhibit spontaneous bleeding (Nakata et al., 2006). IT thanks DVM student Ruby Xu, who provided the basis of this contribution in May 2023.

Molecular genetics

The causative mutation for this disorder was discovered via the candidate gene approach, by Evans et al. (1989), who reported that the mutant allele in the Chapel Hill Cairn Terrier colony is c.1477G>A, resulting in the substitution of glutamic acid for glycine at codon 379 in the factor-IX peptide. This particular site has been highly conserved throughout evolution: there is a glycine at this position in factor IX from human, pig and cattle. Not surprisingly, therefore, this single amino-acid substitution profoundly alters the tertiary structure of the factor-IX molecule, to the extent that no functional factor IX can be detected, which is unusual for a missense mutation . In contrast, a different mutation causes the same disorder in Lhaso Apso dogs: Mauser et al. (1996) reported a deletion of bases 772-776 plus a C>T transition at base 777 in the Auburn colony. In an affected Labrador Retriever, Brooks et al. (1997) reported a deletion of the entire gene. Gu et al. (1999) reported two new mutations - an insertionin exon 8 and another deletion. Brooks et al. (2003) reported a 1.5kb LINE1 insertion in exon 5 associated with a mild form of the disorder. In Rhodesian Ridgebacks, Mischke et al. (2011) reported "a G-A missense mutation in exon 7. This mutation results in a glycine (GGA) to glutamic acid (GAA) exchange [G244E] in the catalytic domain of the haemophilic factor IX" Brenig et al. (2019) reported a mild form of Haemophilia B in a family of Hovawarts, likely caused by "a single nucleotide deletion in the F9 promoter. . . . The deletion is located 73 bp upstream of the F9 start codon in the conserved overlapping DNA binding sites of hepatocyte nuclear factor 4α and androgen receptor." Kuder et al. (2021) described a likely causal variant in the Newfoundland breed: "a single nucleotide insertion resulting in a frameshift in the last exon (NM_001003323.2:c.821_822insA), predicted to result in a premature stop codon (NP_001003323.1:p.Asn274LysfsTer23) with a loss of 178 of 459 amino acids . . . Both the purebred Newfoundland dam and her sister were heterozygous for the insertion. Five additional male offspring developed severe hemorrhage and were hemizygous for the F9 variant and/or had a prolonged aPTT. In contrast, other male littermates had normal aPTTs and no evidence of bleeding."

History

The first reports of this disorder in dogs were on a family of Cairn Terriers diagnosed at the Ontario Veterinary College, Guelph, by Mustard et al. (1960) and Rowsell et al. (1960). The Chapel Hill colony of haemophilia B dogs was established in 1966 from the Guelph animals or their descendants (Sabatino et al., 2012). A colony of Lhasa Apso dogs - the Auburn colony - was first reported by Mauser et al. (1996). Haemophilia B was the first canine disorder to be characterised at the DNA level.

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 306900 Gene · OMIM 300746

Source: OMIA (Nicholas, Tammen & the Sydney Informatics Hub), entry OMIA:000438-9615, 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 B (MONDO:0010604).

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 86.

  1. ★
    In Vivo Gene Therapy of Hemophilia-B - Sustained Partial Correction in Factor-IX-Deficient Dogs · Science · 1993 · PMID 8211118

    Why is this an OMIA Landmark paper? It reported the first use of gene therapy to alleviate the effects of an inherited disorder in OMIA species. In this case, infusion of recombinant retroviral vectors containing cDNA for canine factor IX into the liver of dogs affected with haemophilia B resulted in partial alleviation of the disorder. [FN thanks Hamutal Mazrier for suggestion that the first case of gene therapy in OMIA species is worthy of an OMIA Landmark entry]

  2. ★
    Canine hemophilia B resulting from a point mutation with unusual consequences. · Proc Natl Acad Sci U S A · 1989 · PMID 2481310

    Why is this an OMIA Landmark paper? It provides the first case of a canine Mendelian disorder to be characterised at the DNA level, in this case a missense mutation (c.1477G>A; p. Gly379Glu) in the canine F9 gene. Unusually for a missense mutation, the result is no functional factor IX (possibly because the amino-acid substitution occurs in a highly conserved domain, any changes in which are likely to have a major effect on tertiary structure of the peptide).

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.

Your breed

See what Hemophilia B (Discovered in the Lhasa Apso) looks like in your dog's breed.
Variant frequency by breed

Observed only in small-sample breeds

Maximum variant frequency 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.

Scope of this record

Scope

This record carries the breed-level carrier frequencies from the Donner 2023 cohort. Penetrance data (the fraction of at-risk dogs that develop the phenotype) is not yet quantified for this disease in the Sniff Atlas v1.0.1. The OMIA entry is the authoritative reference for the clinical phenotype, inheritance pattern, and gene assignment.

Predicted disease relevance at the per-dog level is UNPROVEN. The variant frequency is measured; phenotype outcome depends on 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:000438-9615.

  • 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:000438-9615 · Donner et al. 2023 · ClinVar (Landrum 2018)