Evidence of a de novo variant in FBN1:p.(Ala882Val) as the cause of congenital bilateral ectopia lentis in a crossbred horse
Background: Although several inherited ocular disorders have been extensively studied in horses, few reports of equine ectopia lentis exist and no genetic investigations have been performed. Ectopia lentis is reported to be caused by trauma and genetic variants responsible for ocular diseases, and/or systemic diseases in humans and other species. The most commonly reported genetic cause are dominant variants 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 recessive or a de novo mutation was the genetic cause. Results: 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 SNPs 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 fibrillin-1 (FBN1) (FBN1:p.(Ala882Val)). This variant was also computationally predicted to be deleterious to protein function. The affected foal was confirmed by Sanger sequencing to be heterozygous for this variant and his dam, sire, and five paternal half-siblings, all presumed clinically unaffected, were homozygous for the reference allele. Additionally, this same substitution is reported to be pathogenic causing Marfan syndrome in humans with a dominant mode of inheritance, of which ectopia lentis is a common feature. Conclusion: These findings support the de novo hypothesis with a variant in FBN1:p.(Ala882Val) as the likely cause of ectopia lentis in this foal. This is the first report of ectopia lentis caused by a genetic variant in the horse. Given, the role of FBN1 in ectopic lentis in humans and other species, FBN1 should be evaluated as a potential candidate when other horses with this condition are identified.