First reported case of fragile foal syndrome type 1 in the Thoroughbred caused by PLOD1 c.2032G>A.
Abstract: Warmblood Fragile Foal Syndrome Type 1 (WFFS) is an autosomal recessive disorder reported previously only in warmbloods and thought to be caused by a variant in the gene procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1, c.2032G>A, p.Gly678Arg). Given the presentation of this Thoroughbred case, we hypothesised that a similar genetic mechanism caused this phenotype. Objective: To describe the pathological and genetic findings on a foal presenting to a veterinary practice in the UK with skin lesions similar to other Ehlers-Danlos Syndromes, including those documented for warmbloods with WFFS. Methods: A single case report describing a genetic investigation. Methods: A Thoroughbred foal presenting as dystocia was euthanised for multiple skin lesions and developmental abnormalities. DNA extracted from the foal was tested for the PLOD1 variant (c.2032G>A, p.Gly678Arg) using the commercially available assay. To confirm causality and further interrogate potential novel causes of Ehlers-Danlos Syndrome, 1799 functional candidate genes, including PLOD1, were analysed using whole genome sequencing data generated from DNA extracted from the foal's muscle. These data were compared to 34 control samples from at least 11 other breeds. Variants were prioritised for further evaluation based on predicted impact on protein function. Results: Post-mortem evaluation concluded that this foal suffered from a condition of collagen dysplasia. The foal was homozygous for the c.2032G>A PLOD1 variant. Only two other missense variants identified from whole genome sequencing data were also computationally predicted to be deleterious to protein function, (NPHP3 c.1253T>C, p.Leu418Pro, EPDR1 c.154G>C, p.Glu52Gln). Neither of these genes have been linked to similar phenotypes, or Ehlers-Danlos Syndrome in humans or other species and thus further investigation of these variants as the cause of EDS was not warranted. Conclusions: This study is a single case report in the Thoroughbred with no additional cases from this breed yet identified to replicate this finding. Conclusions: Given the clinical presentation similar to WFFS, homozygosity for the PLOD1 variant, and absence of another more plausible causal variant from the WGS experiment, we conclude that PLOD1 c.2032G>A is the likely cause of this foal's condition. This is the first documented evidence of fragile foal syndrome caused by the PLOD1 variant in a breed outside of warmbloods, the Thoroughbred. We therefore recommend 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.
© 2021 EVJ Ltd.
Publication Date: 2022-02-01 PubMed ID: 34939209PubMed Central: PMC9213567DOI: 10.1111/evj.13547Google Scholar: Lookup
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Summary
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The research reported the first case of Warmblood Fragile Foal Syndrome Type 1 (WFFS), caused by a specific genetic variant, in a breed other than warmbloods—the Thoroughbred.
Background
Warmblood Fragile Foal Syndrome Type 1 (WFFS) is an inheritable disorder previously reported only in warmblood horse breeds. This condition is believed to result from a specific mutation in the gene procollagen-lysine,2-oxoglutarate 5-dioxygenase 1 (PLOD1, c.2032G>A, p.Gly678Arg). The researchers hypothesized that the same genetic mechanism could be causing this condition in a Thoroughbred, given the similarity of symptoms.
Objective
The goal of this study was to investigate the genetic findings and symptoms of a Thoroughbred foal that presented with skin lesions similar to Ehlers-Danlos Syndromes, which are also observed in warmbloods with WFFS.
Methods
- A Thoroughbred foal exhibiting dystocia (abnormal or difficult birth) was euthanised due to multiple skin lesions and developmental abnormalities.
- DNA was extracted from the deceased foal and tested for the PLOD1 variant using a commercially available assay.
- In order to confirm the cause and explore potential novel causes of Ehlers-Danlos Syndrome, 1799 functional candidate genes, which included PLOD1, were analyzed using whole genome sequencing data.
- These data were then compared to 34 control samples from a minimum of 11 other horse breeds.
- The team prioritized variants for further study based on their predicted impact on protein function.
Results
- Post-mortem evaluation concluded that the foal had a condition of collagen dysplasia.
- The foal was homozygous (possessing two identical forms of a particular gene) for the c.2032G>A PLOD1 variant.
- Only two other genetic variants were computationally predicted to cause harmful effects to protein function, NPHP3 and EPDR1.
- Neither of these genes have been linked to Ehlers-Danlos Syndrome, or similar symptoms in humans or other species, and were not further investigated.
Conclusions
- This unique case report in the Thoroughbred provides valuable information, even though no other cases of this breed with the same condition are known yet.
- Considering the foal’s clinical presentation, which was similar to WFFS, and homozygosity for the PLOD1 variant, the study concluded that the PLOD1 mutation is likely the cause of the observed symptoms.
- This is the first time that Fragile Foal Syndrome caused by the PLOD1 variant has been documented in a breed other than warmbloods, in this case, the Thoroughbred.
- Because of these findings, the authors suggest renaming the condition to Fragile Foal Syndrome type 1 (FFS) and recommend the use of genetic testing in Thoroughbreds to avoid producing foals with the syndrome.
Cite This Article
APA
Grillos AS, Roach JM, de Mestre AM, Foote AK, Kinglsey NB, Mienaltowski MJ, Bellone RR.
(2022).
First reported case of fragile foal syndrome type 1 in the Thoroughbred caused by PLOD1 c.2032G>A.
Equine Vet J, 54(6), 1086-1093.
https://doi.org/10.1111/evj.13547 Publication
Researcher Affiliations
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Equine Pregnancy Laboratory, Comparative Biomedical Sciences, Royal Veterinary College, Hertfordshire, UK.
- Equine Pregnancy Laboratory, Comparative Biomedical Sciences, Royal Veterinary College, Hertfordshire, UK.
- Rossdales Laboratories, Newmarket, UK.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Animal Science, College of Agricultural and Environmental Sciences, University of California-Davis, Davis, California, USA.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
MeSH Terms
- Animals
- Collagen
- Dioxygenases
- Ehlers-Danlos Syndrome / genetics
- Ehlers-Danlos Syndrome / pathology
- Ehlers-Danlos Syndrome / veterinary
- Horse Diseases / genetics
- Horse Diseases / pathology
- Horses
- Humans
- Ketoglutaric Acids
- Lysine
- Procollagen
- Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / genetics
Grant Funding
- T35 OD010956 / NIH HHS
- UC Davis International Externship Grant
- Alborada Trust
- UC Davis Veterinary Genetics Laboratory
Conflict of Interest Statement
Authors’ declarations of interest. A.S. Grillos, N.B. Kingsley, and R.R. Bellone are affiliated with the UC Davis Veterinary Genetics Laboratory, which provides genetic diagnostic tests in horses and other species.
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