Thirty-eight breeds tested for gene variant behind Warmblood fragile foal syndrome

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The skeleton of the Arabian stallion Bairactar Or. Ar. (1813-1838) in the Stud Museum Offenhausen in Germany. A tooth from this skeleton was used for DNA analysis, and he was eliminated as the purported source of Warmblood fragile foal syndrome. Photo: Stephan Kube

A study in which 4081 horses from 38 breeds were tested for the gene responsible for Warmblood fragile foal syndrome found an overall prevalence of 4.9%.

Warmblood fragile foal syndrome is a recessive disorder, caused by a variant in the PLOD1 gene. Being recessive, it must be inherited from each parent for the condition to emerge in foals.

Affected foals are either naturally aborted, stillborn, or euthanized. The distressing syndrome causes defects in connective tissue, meaning affected foals have hyper-extendible, abnormally thin, fragile skin that tears easily.

Simone Reiter and her fellow researchers reported that the syndrome affected mainly Warmbloods, with a carrier frequency as high as 17% in the Hanoverian and Danish Warmblood.

The average carrier frequency across the 1610 Warmblood horses tested in the study was 11%. Among Warmbloods, the gene variant was present in 17 of the 19 breeds studied.

The researchers, reporting in the journal Genes, said the gene variant was not detected in most non-warmblood breeds, with only a handful of exceptions.

They confirmed its previously reported presence in the Thoroughbred, with 17 of the 716 Thoroughbreds identified as carriers.

It was also found among Haflingers (2 of 48 animals tested), the American Sport Pony (1 in 12), and Knabstrupper horses (3 in 46).

Warmblood fragile foal syndrome (WFFS) genotyping summary for all investigated breeds with the calculated carrier frequency, allele frequency, and 95% confidence interval for allele frequency.
Warmblood fragile foal syndrome (WFFS) genotyping summary for all investigated breeds with the calculated carrier frequency, allele frequency, and 95% confidence interval for allele frequency.
* Thoroughbreds sampled in Poland and firstly published in this article. ** Thoroughbreds already published in Bellone et al., 2019 [30]. Data in italic font denote breeds with small sample sizes (n < 30). Values for the total data set are given in bold.
The American Sport Pony and Knabstrupper have Warmblood genetics in their breed lineages. “Given the Warmblood influence in these breeds, this finding was not surprising,” the researchers said.

The discovery of the gene variant in two Haflingers was surprising, however. Haflingers trace their origins to Europe, with influence from several breeds.

The researchers inspected the pedigree records of the two carriers but did not identify a common ancestor. “However, one of the carriers had six unknown ancestors listed in the six-generation pedigree.”

“The Haflinger breed was developed in Austria and Northern Italy with the foundation sire foaled in 1874, an offspring of a half-Arabian stallion.

The studbook was closed in 1946. It is possible that, before this, an infusion of European Warmblood or Thoroughbred bloodlines could account for the gene variant being present in the Haflinger breed, they said.

So far, its source in the breed remains unknown, and further evaluation of the genetic contribution by other breeds to the Haflinger remains to be investigated.

Researchers were surprised to find the WFFS gene in the Haflinger breed. Image by Adéla Holubová

The study team also tested the 200-year-old remains of a famous Arabian stallion, which ruled him out as the source of the faulty gene.

Bairactar Or. Ar. was born in 1813. His offspring were reported to have a similar condition and he was suggested as the origin.

The study team extracted DNA from a molar removed from his skeleton, which is on display at the Stud Museum Offenhausen in Germany. Analysis showed he did not carry the mutated gene variant.

This result, together with no evidence of the gene variant among the 302 Arabian horses tested as part of the wider study, does not support an Arabian origin for the syndrome.

The authors said that, based on their large dataset, they confirmed that, with exception of the Thoroughbred and the Haflinger, the gene variant is found mainly in Warmblood breeds or those deriving from, or allowing outcrosses, to Warmbloods.

The origin of the mutant gene remains unknown, they said

There is evidence for its origin in the Thoroughbred, because of the occurrence of the gene variant in this breed and the large influence of Thoroughbreds in Warmblood genetics.

The stallion Bay Ronald XX or his son Dark Ronald XX had been suggested as a source, but genetic testing of the skin remains of Dark Ronald XX excluded the line as the source.

The authors said their findings further support the use of genetic testing for the gene variant in Warmblood breeds to prevent the production of affected foals.

“DNA test results can be utilized to avoid mating between carriers while still retaining carriers in the breeding program to maximize diversity and the production of other desirable traits.”

Given the presence of the gene variant in the Knabstrupper and American Sport Pony, it is also advisable to test breeding animals from Warmblood-derived breeds or from breeds where crossing to Warmbloods is allowed, they said.

“DNA screening should even be performed in those breeds that may have genetic influence from Warmblood breeds.”

“Screening for genetic diseases such as Warmblood fragile foal syndrome is not only of significant economic importance but it is also essential to avoid animal suffering,” they said.

The proper use of genetic testing in marker-assisted selection to prevent disease traits in horses cannot be over-emphasized, they said.

The full study team comprised Reiter, Barbara Wallner, Gottfried Brem, Elisabeth Haring, Ludwig Hoelzle, Monika Stefaniuk-Szmukier, Bogusława Długosz, Katarzyna Piórkowska, Katarzyna Ropka-Molik, Julia Malvick, Maria Cecilia Penedo, and Rebecca Bellone.

They are variously affiliated with the University of Veterinary Medicine Vienna, the University of Vienna, the Museum of Natural History in Vienna, the University of Hohenheim in Germany, the University of Agriculture in Kraków, Poland, the National Research Institute of Animal Production in Poland, and the University of California, Davis.

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 2020, 11, 1518.

The study, published under a Creative Commons License, can be read here

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