A novel variant in the VWF gene is associated with von Willebrandt Disease Type II

Von Willebrand disease is the most common inherited bleeding disorder in dogs, caused by deficient or defective plasma von Willebrand Factor (vWF), a blood clotting protein. Five different genetic variants in the vWF encoding gene have been previously associated to different forms of vWD: Type I, Type II and Type III in dogs. The study published earlier this month, suggest a novel variant as a candidate causal variant for vWD Type II in German Shorthaired Pointer and German Wirehaired Pointer (Vos-Loohuis M et al., 2017).

Previously, a variant c.4937G of the canine VWF gene was associated with vWD Type II, an autosomal recessive disorder in German Shorthaired Pointer and German Wirehaired Pointer (Kramer JW et al., 2004). This variant has since also been found in additional breeds, by our laboratory (Donner J et al., 2016) and others. Identification of Chinese Crested Dogs carrying two copies of this variant without clinical manifestation prompted researchers of the University of Utrecht to re-study the VWF gene in pointers manifesting vWD Type II and as a result a scientific publication was released this month describing a novel c.1657G variant in these dogs that is fully linked with the c.4937G variant in both Pointer breeds. This novel variant resides in a more evolutionally conserved area of the gene and was predicted to be damaging for the function of vWF. Moreover, this novel variant was not present in Chinese Crested Dogs, and thus is the strongest candidate for the causal variant responsible of vWD Type II in Pointers. Unfortunately, the previous study performed in 2004 did not include screening of the full coding sequence of VWF gene explaining why the second variant was not discovered earlier. The original c.4937G variant, currently included in the MyDogDNA/Optimal Selection panel, has been and continues to be an effective linked marker to detect the vWD Type II status in both Pointer breeds, but it’s likely that these two variants are not co-segregating on different breed backgrounds, as seen in Chinese Crested Dogs. It remains to be discovered in which other breeds the c.4937G variant is present and predictive of presence of the c.1657G variant or susceptibility to vWD Type II.

All variant findings in additional breeds discovered by the MyDogDNA/Optimal Selection panel test are confirmed with a secondary technology, and presented as a “New Potential Disorder in the Breed”. For a newly detected variant to be considered a “Known Disorder in the Breed”, the requirement by our standards is that the variant was originally scientifically described in the breed or has been later clinically validated in the breed through our own follow up studies. Genoscoper Laboratories as well as other laboratories have identified the c.4937G variant, predictive of vWD status in Pointers, in additional breeds. In accordance with our standards, clinical studies on potentially vWD Type II affected individuals from several breeds have been conducted with willing dog owners through our laboratory. In addition, we have been inviting dogs diagnosed with other hematological disorders to participate in research (http://www.mydogdna.com/blog/clinical-perspective-bleeding-disorders).

Our clinical studies have identified altered levels of vWF in one additional breed while studies are on-going in a number of other breeds. However, in alignment with the recent publication from the University of Utrecht, two Chinese Crested Dogs with two copies of the previously described variant c.4937G did not show signs of a vWF deficiency. In the additional breed, where the concentration of VWF was altered, our research team will next be testing for the presence of the candidate causal variant c.1657G to further validate the role of this variant in the clinical manifestation of vWD Type II. Also, it will be carefully explored if the linked marker is useful to identify potential additional breeds affected with vWD Type II. 

Panel screening remains an efficient approach to screen for disease variants in the dog population, not only to identify potential diseases in additional breeds, but also to critically and comprehensively evaluate published disease associations across a wide range of dogs. As we have long advocated, clinical follow up studies are a necessity whenever a disease variant is discovered in an additional breed, and should always be pursued before a disease variant is considered in breeding selections. In the light of the published vWD Type II research from the University of Utrecht, and our own studies, we have decided to only offer the vWD Type II test based on the c.4937G variant as a marker for German Shorthaired and Wirehaired Pointers, and additional breeds where our in-house research indicates that the variant is linked to a clinical vWD Type II phenotype.

 

References:

Kramer JW, Venta PJ, Klein SR, Cao Y, Schall WD, Yuzbasiyan-Gurkan VA. von Willebrand's factor genomic nucleotide variant and polymerase chain reaction diagnostic test associated with inheritable type-2 von Willebrand's disease in a line of german shorthaired pointer dogs. Vet Pathol 41(3):221-228, 2004.

Donner J, Kaukonen M, Anderson H, Möller F, Kyöstilä K, Sankari S, Hytönen MK, Giger U and Lohi H. Genetic panel screening of nearly 100 mutations reveals new insights into the breed distribution of risk variants for canine hereditary disorders. PlosONE, 1(8): e0161005. doi:10.1371/journal.pone.0161005, 2016. Link to publication

Vos-Loohuis M, van Oost BA, Dangel C, Langbein-Detsch I, Leegwater PA. A novel VWF variant associated with type 2 von Willebrand disease in German Wirehaired Pointers and German Shorthaired Pointers. Animal Gen. doi:10.1111/age.12544, 2017.