A de novo FBN1 variant likely causes congenital bilateral ectopia lentis in a crossbred horse.
Abstract: Although several inherited ocular disorders have been extensively studied in horses, few reports of equine ectopia lentis exist and no genetic investigations have been reported. Ectopia lentis in humans and other species is reported to be caused by trauma, genetic variants, and systemic diseases. The most commonly reported genetic causes are dominant alleles in FBN1. Here we examined a 3-day old Oldenburg x Thoroughbred colt due to concerns over bilateral ocular anomalies and hypothesized that either a recessively inherited allele or a dominant de novo allele was the genetic cause. Examination revealed bilateral microphakia and spherophakia with medioventral lens subluxation. Histopathology of the globes was consistent with ectopia lentis. Whole genome sequencing of the affected foal was conducted, and forty-six candidate genes were evaluated for SNVs and small INDELS. Testing both hypotheses, 82 variants were identified, of which 69 were present in publicly available data from 504 horses and not investigated further. Of the 13 remaining variants, two variants were found in 3' UTRs (ADAMTS17 and OAF), ten were intronic, and one was a coding variant located in the FBN1 gene encoding fibrillin-1 (FBN1:p.(Ala882Val)). This variant was also computationally predicted to be deleterious to protein function, including in silico modelling of FBN1 which suggests that 882Val impacts disulfide bond formation by Van der Waals clashing in a hybrid domain of the protein. The affected foal was confirmed by Sanger sequencing to be heterozygous for this variant and his clinically unaffected dam, reportedly unaffected sire, and five paternal half-siblings were homozygous for the reference allele. Additionally, the homologous human substitution is reported to be pathogenic, causing Marfan syndrome with a dominant mode of inheritance, of which ectopia lentis is a common feature. These findings support the de novo hypothesis with FBN1:p.(Ala882Val) as the likely cause of ectopia lentis in this foal, the first genetic explanation for this condition in the horse. Given the role of FBN1 in ectopia lentis in humans and other species, FBN1 should be evaluated as a potential candidate when other horses with this condition are identified.
© 2025. The Author(s).
Publication Date: 2025-10-24 PubMed ID: 41136527PubMed Central: PMC12552744DOI: 10.1038/s41598-025-21139-7Google Scholar: Lookup
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Summary
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Research Overview
- This study identifies a likely genetic cause for congenital bilateral ectopia lentis (displacement of the eye lens) in a young crossbred horse, pinpointing a specific mutation in the FBN1 gene as the probable cause.
Introduction and Background
- Ectopia lentis is a condition where the lens of the eye is dislocated; it can result from trauma, genetic mutations, or systemic diseases.
- In horses, although several inherited eye disorders are known, ectopia lentis has rarely been reported and its genetic basis was previously unexplored.
- In humans and other species, mutations in the FBN1 gene, which codes for the protein fibrillin-1, commonly cause dominant forms of ectopia lentis.
Case Examination
- A 3-day old colt, bred from Oldenburg and Thoroughbred horses, showed abnormal bilateral eye features prompting investigation.
- Clinical findings in the colt included:
- Bilateral microphakia (abnormally small lenses)
- Spherophakia (rounded lenses)
- Medioventral lens subluxation (partial lens dislocation downward and toward the middle)
- Histopathological examination confirmed the lens displacement consistent with ectopia lentis.
Genetic Analysis Approach
- The researchers hypothesized two possible genetic causes:
- A recessive inherited mutation
- A dominant de novo (new) mutation
- Whole genome sequencing was conducted on the affected colt to investigate 46 genes known to be candidates for ocular disorders.
- They detected 82 genetic variants, but 69 were common among a large dataset of 504 horses and thus excluded.
- The remaining 13 variants were further characterized:
- Two variants located in 3’ untranslated regions (UTRs) of ADAMTS17 and OAF genes
- Ten were intronic (non-coding segments within genes)
- One was a missense coding variant in FBN1 gene causing the amino acid substitution p.(Ala882Val)
Significance of the FBN1 Variant
- The FBN1 variant (Ala882Val):
- Predicted to be damaging to protein function by computational tools.
- Structural modeling indicated the substitution disrupts normal disulfide bond formation crucial for fibrillin-1’s stability via unfavorable Van der Waals interactions.
- Confirmed using Sanger sequencing, the affected colt was heterozygous for this mutation.
- The colt’s clinically unaffected dam, sire, and paternal half-siblings did not carry this variant, supporting a de novo origin.
- Additionally, this exact mutation is known in humans to cause dominant Marfan syndrome, a disorder often marked by ectopia lentis.
Conclusions and Implications
- The study concludes the de novo FBN1 p.(Ala882Val) mutation is the most likely cause of congenital ectopia lentis in this horse.
- This is the first report linking a specific genetic mutation to ectopia lentis in horses.
- Given the conserved role of FBN1 in lens stability across species, future cases of ectopia lentis in horses should include screening of this gene.
- This finding may improve diagnostic understanding, enable genetic counseling, or guide breeding practices to mitigate the disorder.
Cite This Article
APA
Esdaile E, Houston K, Till BJ, Sutton RB, Scurrell E, Ling M, Hartley C, Bellone RR.
(2025).
A de novo FBN1 variant likely causes congenital bilateral ectopia lentis in a crossbred horse.
Sci Rep, 15(1), 37238.
https://doi.org/10.1038/s41598-025-21139-7 Publication
Researcher Affiliations
- Veterinary Genetics Laboratory, University of California, Davis, Davis, CA, USA.
- The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush Campus, Midlothian, UK.
- Veterinary Genetics Laboratory, University of California, Davis, Davis, CA, USA.
- Cell Physiology and Molecular Biophysics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
- Cytopath Ltd, PO Box 24, Ledbury, Herefordshire, UK.
- Cheviot Vets Ltd, Pinnaclehill Industrial Estate, Kelso, UK.
- The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush Campus, Midlothian, UK.
- Veterinary Genetics Laboratory, University of California, Davis, Davis, CA, USA. rbellone@ucdavis.edu.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA. rbellone@ucdavis.edu.
MeSH Terms
- Ectopia Lentis / genetics
- Ectopia Lentis / pathology
- Ectopia Lentis / veterinary
- Animals
- Horses
- Horse Diseases / genetics
- Horse Diseases / pathology
- Male
- Fibrillin-1 / genetics
- Lens, Crystalline / pathology
- Whole Genome Sequencing
Conflict of Interest Statement
Declarations. Competing interests: EE, BJT, and RRB are affiliated with the UC Davis Veterinary Genetics Laboratory, which provides genetic diagnostic testing in horses and other species. No other authors have a conflict of interest. Ethical approval and consent to participate: Hair and blood samples from the affected foal, dam, and his paternal half-siblings were collected under the ethical review provided by the UC Davis Institutional Animal Care and Use Committee as part of Protocol #22786 and experiments were performed according to what was reviewed. A hair sample from the sire was provided by Weatherbys Scientific on behalf of the Coloured Horse and Pony Society (UK) (CHAPS UK) as part of a previously banked sample for registration. The ocular exam and euthanasia were performed at the request of the owner following standard of care and Royal College of Veterinary Surgeons (RCVS) code of practice. Where applicable the study is reported in accordance with ARRIVE guidelines. Consent for publication: The owner of the affected case consented to study and to the data being published.
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