RuffCoast & Meliora

As I’ve come to be an advocate for the preservation of the Drentsche Patrijshond, I’ve endeavored to understand what health issues affect the breed.

One of the most controversial topics currently in the North American Drent community is what, if anything, should be done about von Willebrand Disease in the breed population. Some say it’s not an issue in the breed and will not test for it, while others believe it should be a priority to breed vWD out of the population and that breeding should be regulated accordingly.

When I found out Iris was a carrier of von Willebrand Disease Type 1, I took a special interest in it. As a carrier, she should not be symptomatic but could pass the gene on to offspring. If there was the slightest possibility of having a litter with her, I wanted to understand what her carrier status might mean for that decision. As such, there are four main questions – and related answers – that I pursued and will summarize here, with the intent of sharing the knowledge I’ve gained in a concise yet comprehensive manner.

• What is vWD1? Symptomatically, it is a mild-to-moderate bleeding disorder, characterized by a decrease in the function and/or concentration of a blood clotting agent (vWF).
• How is vWD1 inherited and expressed, generally? Genes that affect vWF production typically follow autosomal inheritance patterns – one copy of the gene is inherited from each parent. In many breeds, it is inherited as autosomal recessive, but in others, it is autosomal dominant. In all, the clinical expression of vWD1 in genetically affected/”at-risk” individuals is not simple nor well understood.
• What do we know about how vWD1 is expressed in Drents? There is limited data on vWD in Drents. While the vWD1 mutant gene is present in the breed, reports of symptomatic individuals are rare.
• What should the Club/Breeders do about vWD1? The Drent is in a population crisis, particularly with epilepsy and genetic diversity. In my opinion, clubs and breeders should prioritize avoiding only the most severe health issues to maintain what little genetic diversity remains, and should endeavor to make thoughtful breeding more accessible to more people, while putting resources towards research and education.

What is vWD1?

Von Willebrand Disease (vWD) is a bleeding disorder caused by genetic mutations that affect the production of an important blood clotting agent called von Willebrand Factor (vWF).

There are three types of vWD, each defined by either a lack of vWF or poorly functioning vWF. Type I is the most common, characterized by a partial deficiency in vWF, which can cause mild-to-moderate bleeding symptoms. Dogs with Type II vWD have a low concentration of vWF, as well as an abnormal structure of vWF. Dogs with Type III may have a complete absence of vWF. Breeds affected by vWD are primarily affected by only one type – Drents are affected by vWD Type 1.

vWF is not the only blood clotting agent, but reduced or dysfunctional concentrations of vWF may lead to easier bruising, nose bleeds, prolonged bleeding periods after losing juvenile teeth or injury, and/or complications in surgery related to increased blood loss. Before necessary surgical procedures, medications can be given to temporarily increase the amount of vWF in the blood to mitigate the risk of complications. Certain medications that interfere with normal blood component functions or concentrations (such as anti-inflammatories) may be avoided to prevent further increasing bleeding risks for dogs affected by vWD. Despite an increase in blood clotting times, most dogs will lead a normal life and have a normal lifespan with this condition.

References:
Cornell Richard P. Riney Canine Health Center
Paw Print Genetics
Shaffer et al., Genetic screening and mutation identification in a rare canine breed, the Drentsche Patrijshond

How is vWD1 Inherited and Expressed?

Genes that affect vWF production typically follow autosomal recessive inheritance patterns – one copy of the gene is inherited from each parent at random, and individuals with two copes of the mutated gene are considered “at risk” for symptomatic vWD.

Parent 1	Parent 2	Offspring
MUT/MUT (“at-risk”)	MUT/MUT (“at-risk”)	MUT/MUT (“at-risk”) (100%)
MUT/MUT (“at-risk”)	MUT/NORMAL (“carrier”)	MUT/MUT (“at-risk”) (50%) MUT/NORMAL (“carrier”) (50%)
MUT/MUT (“at-risk”)	NORMAL/NORMAL (“clear”)	MUT/NORMAL (“carrier”) (100%)
MUT/NORMAL (“carrier”)	MUT/NORMAL (“carrier”)	MUT/MUT (“at-risk”) (25%) MUT/NORMAL (“carrier”) (50%) NORMAL/NORMAL (“clear”) (25%)
MUT/NORMAL (“carrier”)	NORMAL/NORMAL (“clear”)	MUT/NORMAL (“carrier”) (50%) NORMAL/NORMAL (“clear”) (50%)
NORMAL/NORMAL (“clear”)	NORMAL/NORMAL (“clear”)	NORMAL/NORMAL (“clear”) (100%)

In most dog breeds, vWD is autosomal recessive – which means an individual must have mutations/defects in both copies of the gene to be at risk of experiencing clinical symptoms. So, a “MUT/MUT” individual may have blood clotting problems; but “MUT/NORMAL” and “NORMAL/NORMAL” would not. If vWD1 were a simple autosomal recessive trait, we would expect all genetically at risk individuals to experience similarly low levels of vWF, and a similar severity of bleeding issues due to those low levels of vWF.

However, studies show that vWD1 is not a simple autosomal recessive trait. In a study on Doberman Pinschers [Brooks et al.], while the overwhelming majority of clinically affected (ie, symptomatic) dogs were genetically at risk (“MUT/MUT”), not all genetically at risk dogs experienced clinical symptoms. While there was a strong correlation between a genetically at risk dog and a decrease in the concentration of the vWF blood clotting agent, there were many dogs with low vWF concentration who did not experience bleeding issues, despite undergoing similar traumas or surgical procedures as their symptomatic counterparts.

This makes vWD1 a genetic disorder that is “autosomal recessive with incomplete penetrance” – in simple terms, there are other factors at play that we don’t entirely understand yet. Perhaps there are other genes that affect the function or concentration of vWF or other blood clotting agents, epigenetic factors such as stress or diet, or the effect of medications (such as anti-inflammatory blood thinners) that affect the inheritance and/or clinical expression of bleeding issues. These other factors, in addition to the identified genetic mutations, could play into why certain dogs are symptomatic and why other dogs are not. This is why we describe individuals with two copies of the mutated vWD “genetically at risk” rather than “genetically affected“, though these terms are often used interchangeably.

To make matters even more complicated, vWD1 can even show up in some breeds (such as the Kromfohrlander [Segert et al.]) as autosomal dominant with incomplete penetrance – meaning both carriers and genetically affected individuals may or may not be clinically symptomatic.

This type of complex expression is not uncommon in genetics, especially in purebred dogs. Dogs of the same breed in a closed studbook are, to some degree, all related – and thus are likely to share other genes or epigenetics that influence the expression of a particular disease. Therefore, knowing how a particular disease affects one breed may give us clues, but it does not necessarily give us a full understanding of how that disease shows up in another breed. In a conversation between Elinor Karlsson, Ph.D. (of the Vertebrate Genomics Group at the Broad Institute of MIT and Harvard), and Jessica Hekman, DVM, Ph.D., on the Functional Breeding Podcast, Dr. Karlsson explains:

“It turns out whether you get the disease or not, and how severe the disease is, gets influenced by all the other DNA that you carry. […] if you’ve done your study to find this disease variant in one breed or one pedigree from one breed, you have no idea that that same change is going to cause the disease in any other breed.”

Elinor Karlsson, Ph.D.

She goes on to explain that large datasets complete with veterinary records describing clinical expression, not just DNA, are needed to fully understand how a genetic variant/mutation influences symptomatic outcomes. Multiple times throughout the hour, she emphasizes her concern that genetic testing alone should not be used to exclude dogs from breeding based on a misunderstanding of what we truly know and don’t know regarding genetically-influenced diseases, particularly when it comes at a detriment to the breed’s genetic diversity. She ends the podcast with this:

“It I had to get one message to people in the dog breeding world, it would be, ‘Remember that genetics is really, really complicated.‘  The more we look, the more we find. […] And even from a dog breeding standpoint, we might be able to get to a point where we can identify which dogs are okay to breed together and which dogs are going to create puppies that are going to be at really high risk of getting this disease. I would love to get to that point. And we’re not there yet.”

Elinor Karlsson, Ph.D.

References:
Brooks et al., von Willebrand disease phenotype and von Willebrand factor marker genotype in Doberman Pinschers
Segert et al., vWDI is inherited in an autosomal dominant manner with incomplete penetrance, in the Kromfohrländer breed
Functional Breeding Podcast: Genetic Testing from a Scientist’s Perspective

How is vWD1 Expressed in Drents?

A study specifically on Drents by Shaffer et al. (referenced above, and sponsored by the DPCNA through Paw Print Genetics in 2013) establishes that the genetic mutation for vWD1 that has been seen in other breeds is also present in the North American Drent population. They also ran blood tests on two genetically at risk individual Drents and found the expected low concentrations of vWF compared to normal dogs. However, neither of these dogs reported experiencing excessive bleeding symptoms, though at the time, they had not experienced major trauma or surgery.

A separate, unpublished study was done on Drents in the Netherlands (and reported on by the DNA Working Group from the Vereniging de Drentsche Patrijshond to its members) where measurements were taken on the concentration of vWF and compared with buccal mucosa bleeding time (BMBT), a measurement of bleeding time after a cut is made in the upper lip. The study found that a low concentration of vWF was associated with an increase in BMBT compared to normal levels of vWF, but two-thirds of the dogs with low vWF concentration had never clinically experienced symptoms of increased bleeding. Of additional note, these Dutch dogs were not tested for the vWD gene mutation, only the concentration of vWF in their blood.

Both of these studies done on Drents certainly provide clues, but also raise questions on the links between the known vWD gene mutation, actual vWF concentration, and clinical manifestation. Given these questions and the complex expression pattern of vWD1 in other breeds, until further research is done, our understanding of the clinical expression of vWD1 in Drents should be considered incomplete at best. All we know is that a genetically at risk dog may be at risk of experiencing the mild to moderate bleeding symptoms typical of vWD1 in other breeds.

Additionally, the Vereniging de Drentsche Patrijshond (VDPH), the original Dutch breed club for the Drent, has been formally collecting data via a Health Survey since at least 2018. In the three reports publicly released since, the top 6 health issues with the highest incidence are: umbilical hernia (42), allergies (27), epilepsy (26), chronic ear infection (19), undescended testicles (19), and missing teeth (16). There were 9 reported incidences of hip dysplasia and 8 of elbow dysplasia. The health survey reported 20+ additional diagnoses of varying frequency across 616 dogs. “Blood clotting problems” – which may be attributed to von Willebrand Disease (vWD) or other causes – have been reported only twice. Thyroid problems, deviating bites, kink tails, chronic UTIs/anal gland inflammation, and many other diseases and health issues were all reported more frequently.

Reference:
Vereniging de Drenstche Patrijshond Health Survey Reports (You’ll need help from Google Translate!)

What should the Club/Breeders do about vWD1?

It’s important to consider this question in context with other genetically-influenced health issues that also affect the breed, how those health issues effect the quality of life and length of life of dogs affected, and how frequently they show up.

Disease	Effect on Quality of Life	Effect on Length of Life	Frequency of Occurrence
Epilepsy (recurrent, unprovoked seizures)	Moderate -> Severe (can be managed with medication)	Moderate -> Severe	High
Hip Dysplasia (malformation of hip joint resulting in pain & mobility issues)	Mild -> Severe (depending on severity of the dysplasia)	Mild -> Severe (depending on severity of the dysplasia)	Medium
Elbow Dysplasia (malformation of the elbow joint resulting in pain & mobility issues)	Mild -> Severe (depending on severity of the dysplasia)	Mild -> Severe (depending on severity of the dysplasia)	Medium
Progressive Retinal Atrophy (non-painful worsening blindness)	Moderate	None	Low-Med (?)
Allergies (environmental or food-based)	Mild -> Severe (depending on severity of the allergy)	None	High
Hyperuricosuria (high levels of uric acid that can lead to kidney stones)	Mild -> Moderate (once formed, stones can be difficult to treat – but they can be prevented with medication/diet)	None (if well managed); Moderate/Severe (if unmanaged)	Low-Med (?)
von Willebrand Type 1	None -> Mild (potential extra avoidance of high-risk situations)	None without a trigger; complications from trauma/surgery possible (can be mitigated with medication); no known premature deaths	Low

There are also the huge issues related to the decreasing genetic diversity in the breed that are more difficult to quantify, such as inbreeding depression that causes increased occurrence of other (perhaps yet unknown) recessive disorders, decreased overall lifespan, and increased fertility issues (small litter sizes, difficulty conceiving/whelping, etc).

The Drent population is in crisis. In North America there are approximately 150 dogs – in the past 5 years, there have been 13 litters of Drents (9 of which were produced by two kennels that have since merged, and 2 of which were singletons), resulting in ~10 puppies born each year. Growth of the breed in North America has been dangerously slow. Even in the country of origin, there are only approximately 4500-5000 dogs, with ~325 puppies born each year. To put those numbers in context, there are nearly 100,000 Labrador Retrievers registered just with the AKC every year. The concern of decreasing genetic diversity in the breed (and the frequency of debilitating epilepsy cases) has even led to serious conversations about an outcross program in the Netherlands, which would include opening the studbooks and crossing the Drent with other breeds to add genetic diversity back into the population.

The more that breeding options are restricted based on any/all health issues, the more genetic diversity the breed will lose – and once a genetic line is lost, it is lost forever. We can and should complete health testing and endeavor to carefully select breeding pairs. We also can and should import more dogs and/or frozen semen from Europe to supplement the North American Drent population. However, in addition to the financial, logistical, and cultural obstacles associated with importing, none of the Dutch, Swedish, or Belgian Drent clubs require testing for vWD for breeding. Many foreign dogs go untested, and moreover, these clubs have done more extensive empirical research on the issue of vWD than any individual or club in North America has, and they have determined that, based on our current knowledge, it would not be prudent to restrict the potential breeding pool based on whether a Drent has copies of the vWD mutant gene.

For me personally, health issues that will negatively affect a dog’s quality of life or length of life in a severe way are where I will draw my line. Everything else is a tool – preservation breeding is an art as much as a science, balancing dozens of factors to develop and maintain a population of dogs true to their origin. If we, as lovers of the Drent, wish to save this breed, we need to learn how to understand each others’ differing perspectives and come together as a community to facilitate more research, education, and thoughtful breeding despite those differences of opinion – and that includes, but is not limited to, our perspectives on von Willebrand Disease.

My recommendation for the breed club and breeders is twofold:

Recommendation 1: Find ways to make thoughtful breeding easier, not harder, while avoiding only the most severe health issues and balancing health, conformation, temperament, working ability, and as much genetic diversity as possible.

Hopefully, we can slowly move the needle on less-severe and less-commonly-symptomatic health issues like vWD along the way, and when the population becomes more stable, make a stronger push to breed out ALL health issues. When possible, just as much as breeders should endeavor to select pairings that increase the probability of healthy joints or good hunting ability, breeders should endeavor to produce fewer dogs genetically affected by vWD. But a hard line saying breeders cannot produce ANY genetically affected dogs (particularly when that combination could also produce totally clear dogs, such as a carrier-to-carrier pairing) with a relatively mild health issue will do more harm through it’s negative effect on genetic diversity than good.

If too much emphasis is put on eradicating any/all health issues in the breed too soon, we may lose breed type, temperament, working ability, and most definitely what little genetic diversity still exists. And if we lose those things, then while we may end up with perfectly healthy “Drents” by pedigree, if they don’t look like a Drent or act like a Drent or work like a Drent, those dogs won’t be the Drent that many of us fell in love with. We’ll lose the breed in all but numbers, and that will be just as devastating. Not to mention that with decreased genetic diversity the likelihood of good health would decline along with it, due to known and unknown other diseases that are not selected against.

Recommendation 2: Encourage testing, reporting, and further research on all health issues affecting the breed, including but not limited to, vWD1.

It is clear based on the scientific studies that exist (and the lack thereof) that we do not yet have a full understanding of all the genetic and other factors which affect the clinical expression of vWD1 in purebred dogs generally, let alone in Drents specifically. Rather than regulating the decisions of breeders regarding vWD1, the club’s resources would be better utilized by providing incentives for testing/reporting, funding further scientific studies, and developing educational resources. If further research shows that vWD1 has much more severe consequences for a Drent’s quality of life, or premature deaths due to bleeding issues become commonly and officially reported, we can then put vWD1 on the same plane as epilepsy or joint dysplasia and consider it in breeding choices accordingly.

Some folks may still disagree with me. That’s fine – I encourage them to produce as many vWD clear puppies in their breeding program as they’d like! Everyone has their hill they will die on, and we need folks who care about and champion each of the health issues in the breed, including vWD. But based on the extensive research I’ve done, that is not a hill I will climb.

But I urge individuals to consider how much more effective they will be if they utilize their influence, time, and money toward research & education rather than labeling anyone with a different perspective as unethical. We all want to do our best for the breed – and none of us are clairvoyant – so we are sure to have different perspectives on the “how”. Differences in opinion, much like genetic diversity, could lend strength to the Drent’s preservation – as long as we don’t use those differences to outcast one another.

References:
Population Dynamics in Purebred Dogs – Auna Kaufmann for Project Upland (& special thanks to Auna for speaking at length with me about this topic!)

***Please note that the opinions expressed herein are my own and are not to be construed as a statement on behalf of the whole of the DPCNA Board or membership – as is true of any content on this website.