OMIA 001982-9796 : Ehlers-Danlos Syndrome, type VI (Fragile Foal Syndrome) in Equus caballus

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 225400 (trait) , 153454 (gene)

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: Fragile Foal Syndrome Type 1

Species-specific symbol: FFS

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.

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."

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, Warmblood.

Associated gene:

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

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

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.

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
Warmblood Fragile Foal Syndrome PLOD1 missense Naturally occurring variant EquCab3.0 2 g.39927817C>T c.2032G>A p.(G678R) 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

References


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.
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.
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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