Click here for Price and Turnaround Time
Phenotype: Fragile foal syndrome (FFS) type I is an inherited connective tissue defect characterized by lax and hyperextensible joints and abnormally thin, fragile skin and mucous membranes causing extensive lesions throughout the body. This is a lethal condition.
Mode of Inheritance: Autosomal recessive
Alleles: N = Normal/Unaffected, FFS = Fragile foal syndrome
Breeds appropriate for testing: Warmblood breeds, Thoroughbred, Knabstrupper, American Sport Pony, Haflinger
Explanation of Results:
- Horses with N/N genotype will not have fragile foal syndrome and cannot pass this fragile foal syndrome variant to their offspring.
- Horses with N/FFS genotype will not have fragile foal syndrome, but are carriers. They may transmit this fragile foal syndrome variant to 50% of their offspring. Matings between two carriers will result in a 25% chance of producing a fragile foal syndrome-affected foal.
- Horses with FFS/FFS genotype will have fragile foal syndrome, a fatal genetic defect of connective tissue.
Fragile foal syndrome (FFS) type I, formerly known as Warmblood fragile foal syndrome (WFFS) type I, is a fatal genetic defect of connective tissue characterized by hyperextensible, abnormally thin, fragile skin and mucous membranes (tissue that lines cavities and covers organs) that cause extensive lesions throughout the body. Other signs of the disease include hyperextension of limb articulations, floppy ears, hydrops (accumulation of fluid in fetus), subcutaneous emphysema, hematomas, and premature birth. Signs of the disease are present from birth. Newborn foals are euthanized because of poor prognosis for an untreatable condition.
FFS is caused by a mutation (c.2032G > A) in the PLOD1 gene (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1) that codes for an enzyme important for the biosynthesis of collagen, which are complex molecules that provide strength and support to many body tissues. The mutation impairs normal function of the enzyme, which leads to development of the disease. In humans, mutations in this gene are associated with a similar defect known as Ehlers-Danlos Syndrome Type VI.
FFS is inherited as an autosomal recessive defect, which means that both males and females are equally affected and that two copies of the mutation (FFS/FFS) are needed to cause the disorder. Horses that carry one copy (N/FFS) of this recessive mutation are normal but can transmit the mutation to 50% of their offspring.
Testing for FFS allows clinicians to confirm diagnosis of FFS. The test benefits breeders and owners to identify carriers of FFS and to select mating pairs accordingly to avoid producing affected foals. Mating between two carriers has a 25% chance of producing affected foals.
Research at the VGL had identified a low allele and carrier frequency of the FFS mutation in Thoroughbreds. In studying over 700 horses, carrier frequency was 2.4%, meaning out of 200 horses approximately 5 would have one copy of the mutation. The first report of an affected Thoroughbred foal, homozygous for the fragile foal variant (FFS/FFS), has been recently published in the Equine Veterinary Journal. The report resulted from a collaboration between the UC Davis Veterinary Genetics Laboratory and the Royal Veterinary college and was written by UC Davis veterinary student, Alexandra Grillos under mentorship of VGL director Dr. Rebecca Bellone. The identification of an affected Thoroughbred foal provides evidence that the condition is of concern to all horse breeds that carry the mutation and supports the use of genetic testing to inform breeding decisions and avoid producing affected foals.
A recent survey of 38 breeds in the USA and Europe detected the allele in 21 breeds and provided data on allele and carrier frequency in warmbloods as well as several non-warmblood breeds. An expanded table with frequencies listed by breed can be viewed below:
- Click to view FFS allele and carrier frequencies across breeds
Breed Specific Fragile Foal Allele Frequencies
Presented are the data for those breeds in which the FFS variant has been detected. Excerpt from Reiter et al., 2020. For additional information on breeds investigated to date, please visit https://www.mdpi.com/2073-4425/11/12/1518.
Breed Total Carriers Carrier Frequency % Allele Frequency % 95% CI of FFS Allele Frequency American Sport Pony 12 1 8.33 4.17 American Warmblood 57 8 14.04 7.02 3.41 to 13.43 Baden-Württemberger 3 1 33.33 16.67 Belgian Sport Horse 10 1 10.00 5.00 Belgian Warmblood 44 5 11.36 5.68 2.14 to 12.93 Canadian Warmblood 29 3 10.34 5.17 Danish Warmblood 127 22 17.32 8.66 5.74 to 12.82 Dutch Warmblood 249 19 7.63 3.82 2.42 to 5.92 Haflinger 48 2 4.17 2.08 0.12 to 7.74 Hanoverian 283 49 17.31 9.01 6.90 to 11.67 Hessen 2 1 50.00 25.00 Holsteiner 132 11 8.33 4.17 2.26 to 7.39 Knabstrupper 46 3 6.52 3.26 0.72 to 9.55 Lesser Poland Warmblood 157 3 1.91 0.96 0.19 to 2.91 Oldenburg 219 34 15.53 7.76 5.58 to 10.68 Rheinland 12 2 16.67 8.33 Selle Français 52 3 5.77 2.88 0.62 to 8.50 Silesian Horse 96 12 12.50 6.25 3.51 to 10.71 Thoroughbred ** 716 17 2.37 1.19 0.73 to 1.91 Trakehner 64 1 1.56 0.78 0.01 to 4.73 Westfalen 47 2 4.26 2.13 0.12 to 7.89 total 4081 200 4.90 2.47 2.16 to 2.84
** Thoroughbreds as previously reported in Bellone et al., 2019.
Data in italic font denote breeds with small sample sizes (n < 30).
Testing recommendation: The test is presently recommended for all Warmblood/Sport Horse populations and Thoroughbreds given that affected foals have been reported in those breeds. The incidence of carriers in Warmblood horses is estimated to be around 9-11%. Additionally, since the FFS allele has also been detected in the Thoroughbred, Knabstrupper, American Sport Pony, and Haflinger, albeit at low frequencies, testing could inform mating decisions to avoid breeding carriers.
Type of Test
|Test Result||Fragile Foal Syndrome (FFS) Type I|
|N/N||No copies of the FFS mutation. Animal is normal.|
1 copy of the FFS mutation. Animal is normal but is a carrier. Horse can pass on the mutation to 50% of offspring.
2 copies of the FFS mutation. Horse is affected.
Winand, N. Identification of the causative mutation for inherited connective tissue disorders in equines. United States Department Of Commerce Application Number: 61/486,464; (Filing Date: May 16th, 2011).
Monthoux, C., de Brot, S., Jackson, M., Bleul, U., & Walter, J. (2015). Skin malformations in a neonatal foal tested homozygous positive for Warmblood Fragile Foal Syndrome. BMC Veterinary Research, 11(1), 12. doi: 10.1186/s12917-015-0318-8
Bellone, R., Ocampo, N., Hughes, S., Le, V., Arthur, R., Finno, C., & Penedo, M. (2019). Warmblood fragile foal syndrome type 1 mutation (PLOD1 c.2032G>A) is not associated with catastrophic breakdown and has a low allele frequency in the Thoroughbred breed. Equine Veterinary Journal. doi: 10.1111/evj.13182
Reiter, S., Wallner, B., Brem, G., Haring, E., Hoelzle, L., Stefaniuk-Szmukier, M., Długosz, B., Piórkowska, K., Ropka-Molik, K., Malvick, J., Penedo, M.C.T., Bellone, R.R. (2020). Distribution of the Warmblood Fragile Foal Syndrome Type 1 Mutation (PLOD1 c.2032G>A) in Different Horse Breeds from Europe and the United States. Genes, 11(12):1518. doi: 10.3390/genes11121518
Grillos, A., Roach, J., de Mestre, A., Foote, A., Kinglsey, N., Mienaltowski, M. and Bellone, R. (2022). First reported case of fragile foal syndrome type 1 in the Thoroughbred caused by PLOD1 c.2032G>A. Equine Veterinary Journal. Accepted Author Manuscript. doi: 10.1111/evj.13547