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Although horse people have known for decades that some breeds are affected by genetic diseas-es, the sport-horse industry has been content in the knowledge that the warmblood breeds

are free from such disorders.Until this year.The case of a Texas foal born with the almost unheard-of

disease called warmblood fragile-foal syndrome (WFFS), a severe genetic defect, led to the realization that this “sleep-er” disorder has actually been lurking in some warmbloods’ DNA for over 100 years. (See “The Foal That Changed the Warmblood World” on page 37.)

Sport-horse breeders and veterinary researchers are working to publicize the issue and to effect industry change.

Advocates say that warmblood breeders, buyers, and regis-tries alike need to educate themselves about WFFS and to take steps to halt its spread. Read on for an overview of the disorder and a look at how breeders are responding.

Genetics 101To understand what WFFS is and how it proliferates, start with this genetics refresher.

The color of your eyes and your horse’s coat color are examples of genetic traits, or inherited characteristics. Ge-netic diseases, like genetic traits, are passed on to the off-spring from one or both parents.

Some genetic traits are dominant, while others are re-cessive. A dominant trait is passed directly from parent

Special RepoRt

Little known until this year, warmblood fragile-foal syndrome is rocking the sport-horse world. An overview of WFFS and how breeders are fighting back.

BY HEATHER SMITH THOMAS

Genetic Disease Strikes the Warmblood Breeds

ROLLING THE DICE: Genetics is an odds game

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to offspring. A recessive trait appears only if both parents not only carry that recessive gene, but also pass it to the offspring. That’s why a recessive trait may “hide” for many years and suddenly appear as if out of nowhere, like the sur-prise of a red-headed baby born into a brown-haired family.

Genetic diseases or defects result from gene mutations. Mutations occur from time to time as species reproduce, and “there is no way to avoid them, so it is important to stay on top of them,” says retired Cornell University veterinary molecular geneticist Nena Winand, DVM, PhD. But that’s hard to do when the genetic disease is recessive. “By the time a recessive genetic defect is recognized,” she explains, “carrier status for the trait may have already become wide-spread in breeds or closed breeding populations.”

WFFS ExplainedWFFS is a recessive genetic disease that manifests as a con-nective-tissue disorder in affected warmblood foals. WFFS foals have extremely fragile skin that lacks normal durabil-ity and strength, tearing or ulcerating at the lightest contact. In addition, their limb joints are so abnormally lax that they cannot stand. Mares frequently abort WFFS foals, but those that are carried to term must be euthanized soon after birth.

Veterinary researchers and warmblood breeders are beginning to connect the dots between WFFS and foal loss in the warmblood breeds, says Duncan Peters, DVM, DACVSMR, founder and co-owner of East-West Equine Sports Medicine in Lexington, Kentucky, and resident vet-erinarian/consultant for the Lexington-based sport-horse breeding facility Spy Coast Farm.

“Some mares that suffer early pregnancy loss or abort may have this condition,” Peters says, meaning that they may be WFFS carriers. “Some of the warmblood-breeding operations are starting to look into this, checking back through their breeding records to figure this out.”

How Was WFFS Discovered?In the 1990s and early 2000s at Cornell, Winand was re-searching various hereditary genetic defects in equines and other species, including humans. One, hereditary equine re-

gional dermal asthenia (HERDA), causes skin fragility and is found primarily in some lines of American Quarter Horses that trace back to a popular stallion that originated the defect.

“One thing HERDA taught us,” says Winand, “is that recessive traits may exist in horse populations for decades before they are recognized as a problem.”

In 2007, a veterinary researcher at the University of Guelph in Canada contacted Winand and her Cornell col-league William H. Miller Jr., VMD, a professor of veterinary dermatology, about a Hanoverian foal that had been pre-sented for necropsy to a Canadian laboratory. The foal had suffered from a strange combination of severe defects: ex-treme joint laxity and skin that tore like tissue paper at the slightest touch.

The dead foal’s breeder provided blood samples from the sire and dam and from other horses at the facility. “I processed the blood samples for DNA isolation,” says Wi-nand, “but this project had to stay on the back burner be-cause it didn’t give me an avenue to study anything. This material stayed in the freezer a long time.”

The samples came out of the freezer in a hurry in 2011, when Winand and Miller got a call from the Wisconsin Equine Clinic & Hospital in Oconomowoc, Wisconsin, about a warmblood foal that it had just euthanized. The foal had been born with the same set of gruesome defects as the Canadian Hanoverian foal.

Provided with tissue material from the dead Wisconsin foal, Winand set to work. Within 24 hours, she says, she had identified a “devastating” homozygous mutation in a gene. The stallion owners refused to provide Winand with DNA material, she says, but she was able to obtain a blood sample from the dam.

“The dam was heterozygous for that mutation, which means it was probably a recessive trait that had to come from both parents,” she says.

Winand then tested her stored samples provided by the Canadian Hanoverian breeder. “Sure enough, both the sire and dam of that foal were carriers of the same muta-tion—evidence that this mutation is causing the very severe connective-tissue fragility,” she says.

Winand had to do a deep dive into equine family trees to

TELLTALE SIGNS: The skin of foals with warmblood fragile-foal syndrome tears abnormally easily (left). Affected foals’ joints are so lax that they are unable to stand (right).

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try to identify the origin of the WFFS mutation. She eventu-ally concluded that the most likely source was a French Thor-oughbred stallion (whose name she declines to mention) “that was used in France and Germany to upgrade the war-horse types of horses being used in the mid-1800s. This was the only common link, but that stallion was used widely…and is in the bloodlines of many [warmblood] registries.”

Rolling the Genetic Dice: How WFFS Is InheritedTo geneticists, a carrier is an individual that possesses an un-expressed, recessive trait or defective gene. In other words, a carrier can pass the recessive gene on to its offspring but itself does not have the trait or defect. That’s why it’s taken researchers a while to get a handle on WFFS—because carri-ers look and act like every other normal, healthy warmblood sport horse. In fact, some known carriers are top performers, both in the dressage arena and as breeding stock.

WFFS is a recessive trait, meaning that both parents must carry the defective gene in order for it to be passed on to the foal. But even when that happens, the foal doesn’t always have WFFS. Here is how the odds shake out.

A WFFS carrier has one normal gene and one recessive, abnormal gene. If a WFFS carrier is bred to a non-carrier, the offspring will be normal because it has inherited a normal gene from the non-carrier parent. However, the odds are 50/50 that that same offspring will be a carrier of the WFFS gene.

It’s a different story when a WFFS carrier is mated with another WFFS carrier. When that happens, there are three possible outcomes. The offspring can be:

1. Normal but a WFFS carrier (50 percent chance)2. Normal and not a WFFS carrier (25 percent chance)3. Afflicted with WFFS as a result of inheriting the ab-

normal gene from both parents (25 percent chance).

Breeders Confront the DiseaseMany sport-horse enthusiasts learned of WFFS in April 2018, when the well-known breeding facility Hilltop Farm, Colora, Maryland, announced that its Hanoverian stallion Sternlicht Hilltop (Soliman de Hus – EM Rhapsody GGF, Rascalino) is a WFFS carrier. While the farm did further investigation into WFFS, Hilltop was removing Sternlicht from its breeding roster for the remainder of 2018, manag-ing director Natalie DiBerardinis stated in the press release.

Hilltop Farm’s decision to test its breeding stallions for warmblood fragile-foal syndrome (WFFS)—which kicked off the publicizing of the disor-

der—resulted from a tragic loss experienced by one of its clients.

In February 2018, Mary Nuttall, co-owner of Southernwood Farm in Conroe, Texas, had to euthanize a WFFS foal born to one of her seasoned and success-ful broodmares, the Westfalen Dorothee (De Kooning – Alabaster, Cor de la Bryere). The attending veterinarians, who had never seen the colt’s horrific symptoms of frag-ile, tearing skin and joints so lax he could not stand, fran-tically began researching and eventually recommended that Nuttall have the foal tested for WFFS. When the test came back positive, Nuttall contacted Hilltop, which is the US semen broker for the sport-horse stallions of Van Olst Horses in the Netherlands. Dorothee’s foal was sired by the Van Olst KWPN stallion Everdale (Lord Leatherdale – Aliska K, Negro).

Having learned that Dorothee was therefore also a WFFS carrier, Nuttall then tested the rest of her breeding stock. “I discovered that one of my foundation mares, born in 1992 in Denmark, was a carrier.… Her fillies and their fillies have tested positive [as WFFS carriers]. I have four out of 10 positives—40 percent of my stock!”

Shaken by the experience and the subsequent discoveries, “I am tired of people saying it’s no big deal and that no one should worry about [WFFS],” Nuttall says. “I think eventually more carriers will show up, and testing will become the norm. I’m glad the registries are starting to take it seriously. It had to come to the surface so people can discuss it and figure out for themselves how they are going to deal with this issue.”

The Foal That Changed the Warmblood World

HEARTBREAKING: This colt, bred by Mary Nuttall, was born with WFFS and had to be euthanized just 36 hours after birth

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“We’d been working with a mare owner who lost a foal this spring,” DiBerardinis says. “It was not a Sternlicht foal, but test results on the foal showed it was positive for WFFS, so we knew her mare was a carrier. Neither of us knew of anyone who had ever tested their breeding stock or knew this problem existed, so we started by testing our Hilltop-owned stallions. I naively thought everything would be fine because we’ve never had a problem—which is everyone’s response to this issue. When we got the test results, Stern-licht’s came back positive as a carrier, so we knew we had to disclose this information.”

Hilltop’s goal in issuing the statement was “to get peo-ple’s attention and start discussion about WFFS and genetic testing,” DiBerardinis says. The move worked: On reading the description of the disease included in Hilltop’s press re-lease, Lisa Lourie, owner of Spy Coast Farm, realized that she’d had a WFFS-affected foal six years ago.

“I immediately gave [DiBerardinis] Spy Coast Farm’s support,” Lourie says.

Since then, Hilltop and Spy Coast have teamed up with another prominent sport-horse breeding facility, Iron Spring Farm in Coatesville, Pennsylvania, says Lourie. Representa-tives are sharing responsibility for duties including research, peer education, and breed-registry communications, she says. Meanwhile, Spy Coast veterinarian Duncan Peters is searching for grant money to fund additional WFFS study.

“We need to determine who will set policies about WFFS going forward,” Lourie says. In the name of transpar-ency and disease control—and in the hope that other breed-ing facilities will follow their lead—the three partner facili-ties have tested their stallions and posted their carrier status online. They have also instituted the requirement that any mare owner wishing to breed to a carrier stallion have the mare tested beforehand, she says. Their ultimate objective is to halt WFFS by ensuring that, from this point forward, no two carriers are ever mated.

Until now the warmblood world has not grappled with genetic diseases, and some in the sport-horse community have been resistant to the idea of testing their stock and publicizing the results, sources say.

“I’ve found that the breeders who understand the ramifi-cations and testing process have either had a connection with other breeds [that have had to deal with genetic diseases],” says DiBerardinis, “or they are dog breeders. For those of us without that background, it’s a new dimension to confront.”

How Prevalent Is the WFFS Gene? Researchers are trying to get a handle on how frequently the WFFS defect occurs.

“We need to find out how prevalent this really is,” says Lourie. “We have a large data set from our own breedings, and now that we know a few of our mares are carriers and can test the stallions we bred to, we’ll see if there is in-creased incidence of early abortion, or whether just being a carrier brings with it any disadvantage.”

“We don’t know why we don’t have hundreds of these babies born,” says Winand. She postulates that because warmbloods are not as inbred as some other horse breeds, the WFFS defect may surface less frequently. “Also, it hasn’t been until recently that we’ve had some popular dressage and sport-horse sires that happened to be carriers. This provided a greater chance of the phenotype emerging.”

Evidence is beginning to indicate that a significant per-centage of the warmblood population may indeed be WFFS carriers. In an initial localized sampling of 100 warmbloods, both imported and American-bred, from various registries, Winand was “astounded” to find that 10 percent of the horses were carriers. Even that number may be conserva-tive: In May, the European animal genetic-testing labora-tory Laboklin “adjusted the carrier frequency in their test population to 19 or 20 percent,” she says.

As Winand has postulated, there may be a correlation between WFFS and pregnancy loss. Testing aborted warm-blood fetuses and ruling out other causes of the lost preg-nancies won’t be easy, she says, but she’s eager to follow up on the hypothesis.

“Premature pregnancy loss happens in various types of EDS [Ehlers-Danlos syndromes], so it would not be surpris-ing to see this with WFFS,” she says.

Breeders Urged to Test Their Stock“When people decide to breed their warmblood mares or keep colts as stallions, they should test those animals, now that we have a test available,” says Peters. “We need to know

Equines aren’t the only species that suffer from genetic skin defects relating to collagen, which is the main component of connective tissue.

“The same mutation occurs in other species and was studied in a human family with an EDS type VI-affected child,” says retired veterinary molecular geneticist Dr. Nena Winand, referring to the Ehlers-Danlos syndromes (EDS), a group of inherited con-nective-tissue disorders generally characterized by abnormally lax joints and stretchy and fragile skin.

Not Just Horses

USDF CONNECTION • December 2018/January 2019 39

if those horses are carriers, to ensure we never breed a car-rier to a carrier.”

“If the mare is not a carrier,” DiBerardinis says to breed-ers, “you can choose whether to ask for that information about the stallion, because you know you won’t produce a foal that expresses the disease.”

“We are not saying people can’t breed their mares to a carrier stallion, or not to breed a carrier mare,” says Lourie. “That would be detrimental to too many people.” Through testing and selective breeding, “we can slowly start weeding out WFFS. The test can guide breeding decisions.”

WFFS Research and DevelopmentIn the future, a test may be developed that could prevent the heartbreak and loss associated with WFFS foals. James MacLeod, VMD, PhD, a genetics expert at the Gluck Equine Research Center at the University of Kentucky in Lexington, “says an assay might be developed fairly readily in which the fluids surrounding an embryo could be tested for WFFS,” Lourie says. As part of the embryo-transfer process, the fluid could be tested after the embryo is flushed. “You’d know the status of an embryo, and then it would be up to the breeder whether to carry a carrier to term,” she says. Even if test re-sults didn’t come back until after the embryo had been im-planted in a recipient mare, “it would give an option to abort an embryo that was going to end up with WFFS.”

The sport-horse breeders we interviewed want to learn from the experiences of those who have dealt with genetic

diseases in other breeds. The defect hyperkalemic periodic paralysis (HYPP) in Quarter Horses is one well-known ex-ample, but genetic diseases also exist in Friesians, Arabians, and other breed populations.

“We are fortunate,” says Lourie, “because Quarter Horse people did this before us and have a directive now. This makes it easier for us to be able to ask, ‘Where are the pit-falls? What direction should we be going?’”

Lourie and her Hilltop and Iron Spring colleagues are encouraged by the fact that the World Breeding Federation for Sport Horses, the international federation of warmblood studbooks, has put a discussion of WFFS on the agenda of its 2018 general assembly, being held this December, and will hold a workshop on genomic selection.

“We hope we can help influence the direction of those talks,” says Lourie. “We’ll see how receptive they are to openly saying whether their stallions are carriers. If we can persuade the registries to get on board and indicate on a horse’s papers that it is a carrier, then the next person who buys that horse would know.”

At press time, several warmblood registries had enacted WFFS-testing requirements for breeding stock, and some have partnered with laboratories to offer the test to stallion and mare owners. Contact your horse’s registry to learn more. s

Idaho cattle rancher and freelance writer Heather Smith Thomas has been writing about horses and cattle, and raising and training horses, for 50 years.

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