Evidence of de novo variant in FBN1as the potential cause of congenital bilateral ectopia lentis in a crossbred horse

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.