OMIA:001982-9796 : kyphoscoliotic Ehlers-Danlos syndrome (kEDS), PLOD1-related in Equus caballus
Categories: Integument (skin) phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 225400 (trait) , 153454 (gene)
Links to MONDO diseases:
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2011
Species-specific name: kyphoscoliotic Ehlers-Danlos syndrome (kEDS), PLOD1-related; Fragile Foal Syndrome; Fragile Foal Syndrome Type 1; Warmblood Fragile Foal Syndrome
Species-specific symbol: kEDS; kEDS-PLOD1; EDS; FFS; WFFS
Species-specific description: Originally this disorder was called Warmblood Fragile Foal Syndrome (WBFFS or WFFS), but with the discovery of the disorder in other breeds, the breed name has since been dropped and called Fragile Foal Syndrome.
This phene has been renamed from "Ehlers-Danlos Syndrome, type VI (Fragile Foal Syndrome)" to "kyphoscoliotic Ehlers-Danlos syndrome (kEDS), PLOD1-related" in OMIA on the basis of the review on human Ehlers-Danlos syndromes by Malfait et al. (2020) [2/6/2022].
History: Monthoux et al. (2015) provided the first description of the "clinical and histopathological findings in a foal confirmed to be homozygous positive for WFFS".
By genotyping a skin sample from the remains of Dark Ronald XX (1905–1928), a Thoroughbred stallion regarded as a likely origin of the c.2032G>A variant, Zhang et al. (2020) were able to show that this ancestor was not a carrier of this variant, and hence "was not the founder of the WFFS causative variant".
Metzger et al. (2020) concluded that "A Hanoverian stallion, Stallion A [born in 1861 into the F/W sire line], was shown to be the major contributor to the wide distribution of the mutant allele in the Warmblood population."
Molecular basis: In a patent application, Winand (2011) documented a likely causal mutation as c.2032G>A, p.Gly678Arg in the PLOD1 gene encoding procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1.
Clinical features: A "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." (Monthoux et al., 2015)
Pathology: "Histologic examination revealed abnormally thin dermis, markedly reduced amounts of dermal collagen bundles, with loosely orientation and abnormally large spaces between deep dermal fibers." (Monthoux et al., 2015)
Prevalence: Dias et al. (2019) reported an 11% carrier frequency of the likely causal variant c.2032G>A in a sample of 374 Brazilian Warmblood horses, and hence an estimated allele frequency of 5.5%.
Bellone et al. (2020) "demonstrated that the PLOD1 c.2032G>A associated with WFFS is present at very low frequency [1.2%] in Thoroughbreds and is not a genetic risk factor for catastrophic breakdown."
Martin et al. (2020): "Among the sampled population 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". Their Tables 1 and S1 provide estimates for individual breeds.
Reiter et al. (2020): "To investigate the breed distribution of the WFFS allele, 4081 horses belonging to 38 different breeds were screened. In total, 4.9% of the horses representing 21 breeds carried the WFFS allele. The affected breeds were mainly warmbloods, with carrier frequency as high as 17% in the Hanoverian and Danish Warmblood. The WFFS allele was not detected in most non-warmblood breeds. Exceptions include WFFS carriers in the Thoroughbred (17/716), Haflinger (2/48), American Sport Pony (1/12), and Knabstrupper (3/46). The origin of the WFFS allele remains unknown."
Rowe et al. (2021): "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."
Following on from the previous reports (above) of the c.2032G>A variant being detected in heterozygous (healthy) Thoroughbreds, Grillos et al. (2022) described the first reported case of a homozygous (affected) Thoroughbred foal. As a consequence, they recommended "a change in the name of this disorder to fragile foal syndrome type 1 (FFS) and utilisation of genetic testing in Thoroughbreds to avoid producing affected foals".
Ablondi et al. (2022): "The frequency of WFFS carriers [of OMIA variant 165] calculated from a pool of 511 randomly selected SWB [Swedish Warmblood] 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".
Elcombe et al. (2022) reported the c.2032G>A variant (OMIA variant 165) at a frequency of less than 1% in the US Thoroughbred population (1988-2019).
Genetic testing: A DNA test based on the Winand (2011) patent became available commercially through Laboklin GmbH&Co.KG, Bad Kissingen, Germany in 2013 (Monthoux et al., 2015).
Breeds: Thoroughbred (Horse) (VBO_0001083), Warmblood breeds.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|PLOD1||procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1||Equus caballus||2||NC_009145.3 (39953350..39926928)||PLOD1||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|165||Thoroughbred (Horse) Warmblood breeds||Fragile Foal Syndrome||PLOD1||missense||Naturally occurring variant||EquCab3.0||2||g.39927817C>T||c.2032G>A||p.(G678R)||rs1136065234||rs1136065234||2015||25637337||rsID and Variant coordinates obtained from Zhang et al. (2020): "g.39927817C>T (rs1136065234; NC_009145.3, Equ-Cab3.0)" c. and p. coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2022||Ablondi, M., Johnsson, M., Eriksson, S., Sabbioni, A., Viklund, Å.G., Mikko, S. :|
|Performance of Swedish Warmblood fragile foal syndrome carriers and breeding prospects. Genet Sel Evol 54:4, 2022. Pubmed reference: 35062868 . DOI: 10.1186/s12711-021-00693-4.|
|Elcombe, M.E., Bellone, R.R., Magdesian, K.G., Finno, C.J. :|
|Prevalence of the RAPGEF5 c.2624C>A and PLOD1 c.2032G>A variants associated with equine familial isolated hypoparathyroidism and fragile foal syndrome in the US Thoroughbred population (1988-2019). Equine Vet J :, 2022. Pubmed reference: 36199159 . DOI: 10.1111/evj.13883.|
|Grillos, A.S., Roach, J.M., de Mestre, A.M., Foote, A.K., Kinglsey, N.B., Mienaltowski, M.J., Bellone, R.R. :|
|First reported case of fragile foal syndrome type 1 in the Thoroughbred caused by PLOD1 c.2032G>A. Equine Vet J 54:1086-1093, 2022. Pubmed reference: 34939209 . DOI: 10.1111/evj.13547.|
|Wobbe, M., Reinhardt, F., Reents, R., Tetens, J., Stock, K.F. :|
|Quantifying the effect of Warmblood Fragile Foal Syndrome on foaling rates in the German riding horse population. PLoS One 17:e0267975, 2022. Pubmed reference: 35901076 . DOI: 10.1371/journal.pone.0267975.|
|2021||Brooks, S.A. :|
|Genomics in the horse industry: Discovering new questions at every turn. J Equine Vet Sci 100:103456, 2021. Pubmed reference: 34030792 . DOI: 10.1016/j.jevs.2021.103456.|
|Flanagan, S., Rowe, Á., Duggan, V., Markle, E., O'Brien, M., Barry, G. :|
|Development of a real-time PCR assay to detect the single nucleotide polymorphism causing Warmblood Fragile Foal Syndrome. PLoS One 16:e0259316, 2021. Pubmed reference: 34748589 . DOI: 10.1371/journal.pone.0259316.|
|Roberts, J.H., Halper, J. :|
|Connective tissue disorders in domestic animals. Adv Exp Med Biol 1348:325-335, 2021. Pubmed reference: 34807427 . DOI: 10.1007/978-3-030-80614-9_15.|
|Rowe, Á., Flanagan, S., Barry, G., Katz, L.M., Lane, E.A., Duggan, V. :|
|Warmblood fragile foal syndrome causative single nucleotide polymorphism frequency in horses in Ireland. Ir Vet J 74:27, 2021. Pubmed reference: 34663462 . DOI: 10.1186/s13620-021-00206-1.|
|Vroman, R., Malfait, A.M., Miller, R.E., Malfait, F., Syx, D. :|
|Animal models of Ehlers-Danlos syndromes: Phenotype, pathogenesis, and translational potential. Front Genet 12:726474, 2021. Pubmed reference: 34712265 . DOI: 10.3389/fgene.2021.726474.|
|2020||Bellone, R.R., Ocampo, N.R., Hughes, S.S., Le, V., Arthur, R., Finno, C.J., Penedo, M.C.T. :|
|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 Vet J 52:411-414, 2020. Pubmed reference: 31502696 . DOI: 10.1111/evj.13182.|
|Malfait, F., Castori, M., Francomano, C.A., Giunta, C., Kosho, T., Byers, P.H. :|
|The Ehlers-Danlos syndromes. Nat Rev Dis Primers 6:64, 2020. Pubmed reference: 32732924 . DOI: 10.1038/s41572-020-0194-9.|
|Martin, K., Brooks, S., Vierra, M., Lafayette, W.T., McClure, S., Carpenter, M., Lafayette, C. :|
|Fragile Foal Syndrome (PLOD1 c.2032G>A) occurs across diverse horse populations. Anim Genet 52:137-8, 2020. Pubmed reference: 33165934 . DOI: 10.1111/age.13020.|
|Metzger, J., Kreft, O., Sieme, H., Martinsson, G., Reineking, W., Hewicker-Trautwein, M., Distl, O. :|
|Hanoverian F/W-line contributes to segregation of Warmblood fragile foal syndrome type 1 variant PLOD1:c.2032G>A in Warmblood horses. Equine Vet J 53:51-59, 2020. Pubmed reference: 32323341 . DOI: 10.1111/evj.13271.|
|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. :|
|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 (Basel) 11:1518, 2020. Pubmed reference: 33353040 . DOI: 10.3390/genes11121518.|
|Zhang, X., Hirschfeld, M., Schafberg, R., Swalve, H., Brenig, B. :|
|Skin exhibits of Dark Ronald XX are homozygous wild type at the Warmblood fragile foal syndrome causative missense variant position in lysyl hydroxylase gene PLOD1. Anim Genet 51:838-40, 2020. Pubmed reference: 32557718 . DOI: 10.1111/age.12972.|
|2019||Dias, N.M., de Andrade, D.G.A., Teixeira-Neto, A.R., Trinque, C.M., Oliveira-Filho, J.P., Winand, N.J., Araújo, J.P., Borges, A.S. :|
|Warmblood Fragile Foal Syndrome causative single nucleotide polymorphism frequency in Warmblood horses in Brazil. Vet J 248:101-102, 2019. Pubmed reference: 31113555 . DOI: 10.1016/j.tvjl.2019.05.002.|
|2015||Monthoux, C., de Brot, S., Jackson, M., Bleul, U., Walter, J. :|
|Skin malformations in a neonatal foal tested homozygous positive for Warmblood Fragile Foal Syndrome. BMC Vet Res 11:12, 2015. Pubmed reference: 25637337 . DOI: 10.1186/s12917-015-0318-8.|
|2011||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).” http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012158711&recNum=1&maxRec=1&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=FP%3A%28WO2012158711%29&tab=PCT+Biblio :, 2011.|
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