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Fragile Foal Syndrome (PLOD1 c.2032G>A) occurs across diverse horse populations

Authors:
  • Etalon Diagnostics

Abstract and Figures

Fragile Foal Syndrome has been found in a variety of horse breeds. As we continue to monitor the incidence of this variant across the horse population it is apparent that the Fragile Foal Syndrome is not limited to Warmbloods as originally thought.
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BRIEF NOTE
Fragile Foal Syndrome (PLOD1 c.2032G>A) occurs across diverse
horse populations
Katie Martin*, Samantha Brooks
, Micaela Vierra*, W. Tyler Lafayette*, Scott McClure
,
Meredith Carpenter* and Christa Lafayette*
*Etalon Inc., Menlo Park, CA 94025, USA.
Department of Animal Science, UF Genetics Institute, University of Florida, Gainesville,
FL 32611, USA.
Scott McClure, Midwest Equine, Boone, IA 50036, USA.
Fragile Foal Syndrome (FFS), originally termed Warmblood
Fragile Foal Syndrome, OMIA 001982-9796, is an autoso-
mal recessive lethal genetic disorder caused by an SNP
(c.2032G>A) in the procollagen-lysine, 2-oxoglutarate 5-
dioxygenase 1 (PLOD1) gene
1
. Homozygous foals, not
aborted or stillborn, exhibit clinical signs including skin
lesions, incomplete closure of the abdominal wall, hyper-
flexion/extension of joints, inability to stand and difficulty
breathing, and usually die or require euthanasia within
72 h of birth.
1
Genetic testing for FFS has been commer-
cially available since 2013.
2
Initially, it was assumed that
FFS was only found in Warmbloods and related breeds,
2
but
recent studies have identified FFS-positive Thoroughbreds.
3
The aim of this work was to make unbiased observations of
the frequency of FFS across horse breeds (Figure 1).
The DNA of 7362 horses submitted for commercial
genetic testing was genotyped for FFS using hair, tissue,
semen or blood samples with owner consent. The QIAGEN
Gentra Puregene Tissue Kit was used to extract DNA from
the samples. The population of horses was thinned of
related horses within one generation, yielding 7343 horses
representing 78 breeds or types of horse (Table S1).
Using this unbiased testing approach, we observed FFS in
a wide group of horse breeds. Among the sampled popu-
lation of 7343 horses of various breeds, the overall FSS
frequency was 0.56%. The FFS frequency in Warmblood
type breeds was 5.32 and 0.45% in other breeds (Table 1
and Table S1).
Metzger and colleagues suggest that FFS originated in the
W/F-line of Hanoverian warmblood horses.
4
In this study,
we observed FFS carriers among diverse populations with
no identifiable common ancestor. These new data suggest
that the founder of this mutation is much older than
proposed by Metzger et al.
In previous studies completed in Germany,
2
Brazil
1
and
the United States,
5
a carrier frequency of around 10%
suggested that more affected foals should be born each year
than are reported, but there are no studies exploring the
frequency of homozygosity of FFS among stillborns and
abortions, nor are breeders accustomed to using genetic
Figure 1 Haflinger Fragile Foal Syndrome
(FFS) carrier ‘Nacho’ (ffs/n) pictured with
owner
Address for correspondence
C. Lafayette, Etalon Inc., Menlo Park, CA 94025, USA.
E-mails: khoefs@etalondx.com, clafayette@etalondx.com
Accepted for publication 12 October 2020
doi: 10.1111/age.13020
1
©2020 Stichting International Foundation for Animal Genetics
testing to explore the reasons for these losses. Thus, the
potential economic impact of this variant on the breeding
industry cannot yet be reliably estimated.
In addition to our population of unrelated horses, we
genotyped a small family consisting of 16 offspring and
sired by an American Paint Horse stallion carrying FFS.
Within this family, we observed 10 (62.5%) FFS carriers,
demonstrating transmission of FFS.
Awareness that FFS is not specific to one breed, and the
utilization of comprehensive unbiased genetic testing
approaches, will aid in the education of breeders and
registries for all breeds. Testing can then be appropriately
employed, allowing breeders to be more informed when
selecting mating pairs and reducing the risk of affected foals
and failed pregnancies. This knowledge will help registries
to refine policies requiring testing prior to breeding, further
ensuring the avoidance of the production of homozygous
FFS offspring, and thus reducing the variant frequency in
populations.
Acknowledgement
The authors would like to thank Regan McClure for
providing a photo of her horse ‘Nacho’ for use in this short
communication.
Availability of data
Six of the authors are affiliated with Etalon Diagnostics,
which offers testing for the FFS variant.
References
Dias N.M. et al. (2019) Vet J 248, 1012.
Monthoux C. et al. (2015) BMC Vet Res 11, 12.
Bellone R.R. et al. (2019) Equine Vet J 52, 4114.
Metzger J. et al. (2020) Equine Vet J,19.
Winand N.J. et al. (2019) Vet J 248, 1012.
Supporting information
Additional supporting information may be found online in
the Supporting Information section at the end of the article.
Table S1. Expanded list of observed frequencies of FFS/n
genotype in Warmblood and non-Warmblood horse breed
populations
Table 1 Observed frequencies of FFS/n genotype in Warmblood and
non-Warmblood horse breed populations.
Breed
1
Total FFS/n Frequency of FFS
Arabian 364 0 0.00%
Draft 866 1 0.12%
Iberian 165 0 0.00%
Other 366 2 0.55%
Other stock 513 3 0.58%
Paint horse 3492 17 0.49%
Pony 64 0 0.00%
Quarter horse 1082 3 0.28%
Thoroughbred 149 0 0.00%
Warmblood 282 15 5.32%
Total 7343 41 0.56%
1
See Supplemental Table S1 for full list of breeds.
©2020 Stichting International Foundation for Animal Genetics, doi: 10.1111/age.13020
Martin et al.2
... To date, two gene defects causing EDLS phenotypes in horses have been discovered, hereditary equine regional dermal asthenia (HERDA), a degenerative inherited autosomal recessive skin disorder occurring in Quarter Horses and related breeds [10], and Warmblood fragile foal syndrome (WFFS), a lethal congenital autosomal recessive disorder, which to date has only been reported in Warmblood foals [11,12]; however, the Open Access *Correspondence: aine.rowe@ucd.ie 1 Veterinary Sciences Centre, School of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Belfield, Dublin 4, Ireland Full list of author information is available at the end of the article WFFS causative mutation has been identified in Thoroughbreds [13,14], Draft Horses, Paint Horses, Quarter Horses [15] and in the American Sport Pony [16]. ...
... In this study the PLOD1 variant was not detected in any Cobs, Standardbreds, Connemara or other Pony breeds tested, although the number of horses tested belonging to these breeds was too low to draw conclusions on breed prevalence. The WFFS allele has been reported in the American Sport Pony [16], Quarter Horse [15] and Draft Horse [15], suggesting that further investigation is required to more accurately determine the prevalence PLOD1 variant in these breeds. ...
... In this study the PLOD1 variant was not detected in any Cobs, Standardbreds, Connemara or other Pony breeds tested, although the number of horses tested belonging to these breeds was too low to draw conclusions on breed prevalence. The WFFS allele has been reported in the American Sport Pony [16], Quarter Horse [15] and Draft Horse [15], suggesting that further investigation is required to more accurately determine the prevalence PLOD1 variant in these breeds. ...
Article
Full-text available
Background Warmblood Fragile Foal Syndrome (WFFS) is an autosomal recessive disorder caused by a mutation in the procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 ( PLOD1 ) gene. Homozygosity for the mutation results in defective collagen synthesis which clinically manifests as the birth of non viable or still born foals with abnormally fragile skin. While the mutation has been identified in non Warmblood breeds including the Thoroughbred, to date all homozygous clinically affected cases reported in the scientific literature are Warmblood foals. The objective of this study was to investigate the carrier frequency of the mutation in the Thoroughbred and sport horse populations in Ireland. Methods A test was developed at the UCD School of Veterinary Medicine using real-time PCR to amplify the PLOD1 gene c.2032G > A variant. A subset of the samples was also submitted to an external laboratory with a licensed commercial WFFS genetic test. Results Warmblood Fragile Foal Syndrome genotyping was performed on hair samples from 469 horses representing 6 different breeds. Six of 303 (1.98%) sport horses tested and three of 109 (2.75%) Thoroughbreds tested were heterozygous for the WFFS polymorphism (N/WFFS). The WFFS polymorphism was not identified in the Standardbred, Cob, Connemara, or other pony breeds. Conclusions The study identified a low frequency of the WFFS causative mutation in sport horses and Thoroughbreds in Ireland, highlighting the importance of WFFS genetic testing in order to identify phenotypically normal heterozygous carriers and to prevent the birth of nonviable foals.
... The lethal WFFS allele has not been detected in most non-warmblood breeds, which supports the exclusivity of the WFFS mutation to Warmbloods and Thoroughbred horses [6,9]. Nevertheless, a recent study found a few WFFS carriers in Paint, Quarter, and Haflinger horses [10]. ...
... Our estimate of the frequency of WFFS carriers among the randomly selected samples (7.4%) was lower than estimates obtained in German and Brazilian Warmbloods [6,7], and across Warmblood breeds [8,10]; however, the two latter studies found no WFFS carriers among the small number of 18 SWB horses sampled. ...
Article
Full-text available
Background Warmblood fragile foal syndrome (WFFS) is a monogenetic defect caused by a recessive lethal missense point mutation in the procollagen‐lysine, 2‐oxoglutarate 5‐dioxygenase 1 gene ( PLOD1 , c.2032G>A). The majority of homozygous WFFS horses are aborted during gestation. Clinical signs of affected horses include fragile skin, skin and mucosa lacerations, hyperextension of the articulations, and hematomas. In spite of its harmful effect, a relatively high frequency of WFFS carriers has been found in Warmblood horses, suggesting a heterozygote advantage. Thus, in this study our aims were to: (1) estimate the frequency of WFFS carriers in the Swedish Warmblood breed (SWB), (2) estimate the effect of WFFS carrier genotype on performance traits in two SWB subpopulations bred for different disciplines, and (3) simulate the potential effects of balancing selection and different selection strategies on the frequency of carriers. Methods In total, 2288 SWB sport horses born between 1971 and 2020 were tested for the WFFS mutation and had estimated breeding values (EBV) for ten traditional evaluating and 50 linear descriptive traits. Results The frequency of WFFS carriers calculated from a pool of 511 randomly selected SWB horses born in 2017 was equal to 7.4% and ranged from 0.0 to 12.0% among the whole set of tested SWB horses, starting from 1971 till 2020. The effect of the WFFS carrier genotype was significant for several EBV mainly related to movements and dressage traits and especially for horses not bred for the show jumping discipline. Using simulation, we showed that balancing selection can maintain a recessive lethal allele in populations such as the SWB breed over generations and that the frequency is expected to slowly decrease in absence of balancing selection. Finally, we showed that selection against carrier sires can result in a more rapid decrease of the frequency of the mutant allele over time. Conclusion Further research is needed to confirm the apparent association between equine performance and the WFFS carrier genotype. Identification of such associations or new causative mutations for horse performance traits can serve as new tools in horse breeding to select for healthy, sustainable, and better performing horses.
... Warmblood fragile foal syndrome (WFFS) is an autosomal recessive genetic condition affecting the connective tissue of Warmblood foals [1]. The disorder is caused by a mutation in procollagen-lysine, 2-oxoglutarate 5-dioxygenase1 (PLOD1) gene [2,3]. The PLOD1 gene encodes for the enzyme lysyl hydroxylase, which is responsible for converting lysine to hydroxylysine through hydroxylation. ...
... Further prevalence studies are required in order to determine the true prevalence of the mutation in the equine population globally. Although typically associated with Warmblood breeds, the mutation has also been identified in non-Warmblood breeds, including the Thoroughbred [7,9,10], Quarter Horse [3] and American Sport Pony [9], highlighting the importance of genetic testing for the mutation, in clinically suspicious cases, in non-Warmblood breeds as well as Warmblood breeds. ...
Article
Full-text available
Warmblood Fragile Foal syndrome (WFFS) is an autosomal recessive condition that affects the maturation of collagen in affected foals. Foals affected with the disease typically die or are euthanised shortly after birth. WFFS is caused by a single nucleotide change at position 2032 of the equine PLOD1 gene, causing an impairment of the wild-type enzyme. A commercial test for the causative genetic mutation is currently available from companies operating under licence from Cornell University but it has limitations. This test requires amplification of a region of the PLOD1 gene encompassing the site of interest, followed by Sanger sequencing of that region and computational analysis. We describe here the development of an alternative, real-time PCR based assay that rapidly and reliably differentiates between the wild-type and WFFS associated nucleotides without the need for sequencing, thus increasing the potential for high throughput analysis of large numbers of samples in a cost-effective manner.
... It is proposed to be an autosomal recessive disorder caused by a single nucleotide variant in the procollagen-lysine-2-oxoglutarate-5-dioxygenase 1 -PLOD1 gene [20] . The Warmblood Fragile Foal Syndrome (WFFS) has been first studied in Warmblood horses, but according to re-cent findings , PLOD1 allele occurred not only in warmblood breeds and thus, it has been postulated to rename FFS [21] . In the present study, tested Selle Francais were heterozygotes for the PLOD1 allele in a percentage of 6% -CT and the mutant allele sowed the frequency 3% ( Table 2 ). ...
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Background Skin malformations that resembled manifestations of Ehlers-Danlos-Syndrome were described in a variety of domestic animals during the last century as cutis hyperelastica, hyperelastosis cutis, dermatosparaxis, dermal/collagen dysplasia, dermal/cutaneous asthenia or Ehlers-Danlos-like syndrome/s. In 2007, the mutation responsible for Hereditary Equine Regional Dermal Asthenia (HERDA) in Quarter Horses was discovered. Several case reports are available for similar malformations in other breeds than Quarter Horses (Draught Horses, Arabians, and Thoroughbreds) including four case reports for Warmblood horses. Since 2013, a genetic test for the Warmblood Fragile Foal Syndrome Type 1 (WFFS), interrogating the causative point mutation in the equine procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1, or lysyl hydroxylase 1) gene, has become available. Only limited data are available on the occurrence rate and clinical characteristics of this newly detected genetic disease in horses. In humans mutations in this gene are associated with Ehlers-Danlos Syndrome Type VI (kyphoscoliotic form).Case presentationThis is the first report describing the clinical and histopathological findings in a foal confirmed to be homozygous positive for WFFS. The Warmblood filly was born with very thin, friable skin, skin lesions on the legs and the head, and an open abdomen. These abnormalities required euthanasia just after delivery. Histologic examination revealed abnormally thin dermis, markedly reduced amounts of dermal collagen bundles, with loosely orientation and abnormally large spaces between deep dermal fibers.ConclusionWFFS is a novel genetic disease in horses and should be considered in cases of abortion, stillbirth, skin lesions and malformations of the skin in neonatal foals. Genetic testing of suspicious cases will contribute to evaluate the frequency of occurrence of clinical WFFS cases and its relevance for the horse population.
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Background: Catastrophic fractures are among the most common cause of fatalities in racehorses. Several factors, including genetics, likely contribute to increased risk for fatal injuries. A variant in the procollagen-lysine, 2-oxoglutarate 5-dioxygenase1 gene (PLOD1 c.2032G>A) was shown to cause Warmblood fragile foal syndrome type 1 (WFFS), a fatal recessive defect of the connective tissue. Screening of multiple horse breeds identified the presence of the WFFS allele in the Thoroughbred. PLOD1 is involved in cross-linking of collagen fibrils and thus could potentially increase risk of catastrophic breakdown. Objectives: Estimate the frequency of the WFFS allele (PLOD1 c.2032G>A) and determine if it is a risk factor for catastrophic breakdown in the Thoroughbred. Study design: Case-control genetic study. Methods: Genomic DNA from hair and/or tissue samples was genotyped for the WFFS allele. Fisher's Exact tests were performed to compare allele and carrier frequencies between the case cohort (catastrophic breakdown, n = 22) and several cohorts with no record of injury (n = 138 raced/trained at same track and season and n = 185 older than 7 years and raced during same season), non-racers (n = 92), and a random sample without consideration for racing history (n = 279). Results: The frequency of the PLOD1 c.2032G>A variant in the Thoroughbred breed is low (1.2%). Seventeen out of 716 Thoroughbreds tested were carriers (2.4%) and no WFFS homozygotes were detected. Only one catastrophic breakdown case carried the WFFS allele. No statistically significant difference in allele or carrier frequency was identified between case and control cohorts (P>0.05 in all comparisons performed). Conclusions: This study demonstrated that the PLOD1 c.2032 G>A associated with WFFS is present at very low frequency in Thoroughbreds and is not a genetic risk factor for catastrophic breakdown.
Article
Warmblood Fragile Foal Syndrome (WFFS)is an autosomal recessive genetic disorder caused by a mutation in the procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1)gene, associated with collagen biosynthesis. WFFS causes lesions and malformations of the skin in neonatal foals, and abortion. The objective of this study was to investigate the allelic frequency of the single nucleotide polymorphism (SNP)c.2032G>A in the PLOD1 gene in warmblood samples from Brazil. Of the 374 Warmblood horses tested, 41 animals (11%)were identified as heterozygous for the WFFS SNP and 333 (89%)were homozygous for the wild-type allele (N/N), and therefore, the allele frequency was 5.5%. This study highlights the importance of control measures to prevent an increase in the incidence of WFFS in Warmblood horses worldwide.
  • N M Dias
Dias N.M. et al. (2019) Vet J 248, 101-2.
  • C Monthoux
Monthoux C. et al. (2015) BMC Vet Res 11, 12. Bellone R.R. et al. (2019) Equine Vet J 52, 411-4.
  • J Metzger
Metzger J. et al. (2020) Equine Vet J, 1-9.
  • N J Winand
Winand N.J. et al. (2019) Vet J 248, 101-2.