In other species: Asiatic elephant

Categories: Haematopoietic system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 227500 (trait) , 613878 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009211: congenital factor VII deficiency

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2005

Cross-species summary: Bleeding disorder due to deficiency of factor VII, a vitamin K–dependent glycoprotein. In humans also called Alexander's disease; proconvertin deficiency; prothrombin conversion accelerator deficiency; hypoproconvertinaemia.

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Callan et al. (2005, 2006) were the first to report a molecular basis for this disorder in dogs, as follows: "a G to A missense mutation in exon 5 in the affected Beagles, resulting in substitution of glycine 96 (GGA) to glutamic acid (GAA) in the second epidermal growth factor-like domain." The same variant (omia.variant:40) was later later reported in several additional breeds (e.g., Kaae et al., 2007; Donner et al., 2016; Thorsrud and Huson, 2021). For some of these breeds affected dogs were reported to be homozygous for the variant. Scottish deerhounds have been reported with Factor VII deficiency (Keeshen et al. 2017), but Court et al. (2023) report that in their study of Scottish deerhounds with delayed postoperative hemorrhage (DEPOH) the F7 c.407 G>A variant was not associated with DEPOH". A missense SERPINF2 variant was associated with DEPOH in their study (see OMIA:002631-9615 : Delayed postoperative hemorrhage in Canis lupus familiaris).

Clinical features: Ramirez et al. (2019) report that the disease results in mild to moderate bleeding propensity, but in most cases it is identified by chance when regular coagulation screenings result in extended prothrombin times (PT). Kaae et al. (2008) report that clinical presentation includes subcutaneous hematoma formation, blood loss anemia, and a history of abnormal bleeding. IT thanks DVM student Rami Mazraani, who provided the basis of this contribution in May 2023.

Prevalence: Clark et al. (2022) genotyped "67 anticoagulant-negative autopsy cases with unexplained etiology for gross lesions of hemorrhage" for the c.407G>A variant (OMIA variant id 40), and reported that "All 67 cases tested homozygous for the wild-type allele, indicating that the common FVIID variant was not responsible for the observed unexplained bleeding."

Genetic testing: Ramirez et al. (2019) "identified 2 polymorphisms near the disease-causing F7 gene mutation, one of which interfered with testing in several Beagles by causing allele dropout of the normal, wild-type allele. In the absence of an external proficiency program among veterinary genetic testing laboratories, implementation of an internal proficiency program, which requires 2 independent methods for genotyping dogs at any given locus, was further enhanced by ensuring minimally non-overlapping primer pairs between the 2 assays. After redesign of our clinical tests, all dogs were re-examined, and the correct genotypes were identified. These changes ensure higher accuracy in future testing of the F7 mutation."

Breeds: Airedale Terrier (Dog) (VBO_0200008), Alaskan Husky (Dog) (VBO_0200015), Alaskan Klee Kai (Dog) (VBO_0200016), Alaskan Malamute (Dog) (VBO_0200017), American Foxhound (Dog) (VBO_0200047), Basset Hound (Dog) (VBO_0200126), Beagle (Dog) (VBO_0200131), Catahoula Leopard Dog (Dog) (VBO_0200298), Dachshund, Miniature Smooth-Haired (Dog) (VBO_0200410), English Foxhound (Dog) (VBO_0200490), Finnish Hound (Dog) (VBO_0200522), German Shorthaired Pointer (Dog) (VBO_0200583), German Wirehaired Pointer (Dog) (VBO_0200602), Giant Schnauzer (Dog) (VBO_0200604), Harrier (Dog) (VBO_0200660), Irish Water Spaniel (Dog) (VBO_0200705), Japanese Spitz (Dog) (VBO_0200740), Miniature Schnauzer (Dog) (VBO_0200896), Mixed Breed (Dog) (VBO_0200902), Papillon (Dog) (VBO_0200985), Redbone Coonhound (Dog) (VBO_0201132), Scottish Deerhound (Dog) (VBO_0201195), Sealyham Terrier (Dog) (VBO_0201200), Welsh Springer Spaniel (Dog) (VBO_0201411), Whippet (Dog) (VBO_0201421).
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: