Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 225400 (trait) , 153454 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0016002: Ehlers-Danlos syndrome, kyphoscoliotic type 1

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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 (Horse) (VBO_0017483).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: