FYCO1 Frameshift Deletion in Wirehaired Pointing Griffon Dogs with Juvenile Cataract

Abstract

Different breed-specific inherited cataracts have been described in dogs. In this study, we investigated an inbred family of Wirehaired Pointing Griffon dogs in which three offspring were affected by juvenile cataract. The pedigree suggested monogenic autosomal recessive inheritance of the trait. Whole-genome sequencing of an affected dog revealed 12 protein-changing variants that were not present in 566 control genomes, of which two were located in functional candidate genes, FYCO1 and CRYGB. Targeted genotyping of both variants in the investigated family excluded CRYGB and revealed perfect co-segregation of the FYCO1 variant with the juvenile cataract phenotype. This variant, FYCO1:c.2024delG, represents a 1 bp frameshift deletion predicted to truncate ~50% of the open reading frame p.(Ser675Thrfs*5). FYCO1 encodes the FYVE and coiled-coil domain autophagy adaptor 1, a known regulator of lens autophagy, which is required for the normal homeostasis in the eye. In humans, at least 37 pathogenic variants in FYCO1 have been shown to cause autosomal recessive cataract. Fcyo1^-/- knockout mice also develop cataracts. Together with the current knowledge on FYCO1 variants and their functional impact in humans and mice, our data strongly suggest FYCO1:c.2024delG as a candidate causative variant for the observed juvenile cataract in Wirehaired Pointing Griffon dogs. To the best of our knowledge, this study represents the first report of a FYCO1-related cataract in domestic animals.

Keywords: Canis lupus familiaris; animal model; lens; ophthalmology; precision medicine; veterinary medicine; whole-genome sequence.

Figure 1

Pedigree of the investigated Wirehaired Pointing Griffon family. All dogs of this pedigree originated in Europe. Filled symbols indicate affected dogs and open symbols indicate nonaffected dogs. Squares and circles represent males and females, respectively. An asterisk indicates the dog that was used for whole-genome sequencing. Genotypes at the FYCO1:c.2024del variant are given for dogs from which samples were available.

Figure 2

Details of the FYCO1:c.2024delG variant. The genomic organization of the FYCO1 gene on chromosome 20 is indicated at the top. At the bottom left, an Integrative Genomics Viewer (IGV) screenshot shows the short-read alignments of the affected and a control dog at the position of the deletion. At the bottom right, representative Sanger electropherograms of an affected and a control dog are shown. The altered reading frame and the premature stop codon of the mutant sequence are indicated in red. More than 50% of the 1459 wildtype codons are truncated.