Submission Details

The EYS gene (the ortholog of the Drosophila “eyes shut” gene) was first reported in relation to autosomal recessive retinitis pigmentosa in 2008 (Collin et al., PMID 18976725 and Abd El-Aziz et al., PMID 18836446). EYS-related retinopathy is estimated to cause 5-16% of cases of inherited retinal degeneration in some populations (PMID 20537394, 33833316), characterized by classic presentation of night blindness and constriction of visual fields in multiple large families. We found EYS-related retinopathy is inherited in an autosomal recessive pattern, with biallelic pathogenic EYS variants causing classic retinitis pigmentosa. However broader phenotypes including cone-rod dystrophy (PMIDs: 18976725, 24652164, 29550188) and macular dystrophy (PMID 31074760) have also been described; age of onset and severity of disease appears to be variable. Because the cases with different diagnoses all exhibit a recessive mode of inheritance and share overlapping phenotypes consistent with a single spectrum of disease, and consistent with criteria outlined by the ClinGen Lumping and Splitting Working Group, these cases have been lumped into a single disease entity, EYS-related retinopathy (MONDO:0800391).

Seventeen variants suspected disease-causing variants (8 predicted null and 7 missense or other variants) that have been reported in 14 probands in 11 publications (PMIDs: 21069908, 18976725, 18836446, 20237254, 24652164, 29550188) were scored in this curation. Homozygous variants in families from multiple countries were included in the curation (PMID 20537394, 21069908, 18836446) from both consanguineous and non-consanguineous families. However, missense variants have also been associated with EYS-related disease in multiple publications (PMID 20237254). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

The mechanism of pathogenicity appears to be loss of function, as multiple nonsense or frameshift variants resulting in EYS-related disease are described in the literature (PMID: PMID 20537394, 21069908, 18836446). However, missense and splicing variants are also reported to be associated with disease (PMID 20237254). While genotype-phenotype correlations have not been well established, pathogenic variants in the conserved C-terminal portion of the amino acid sequence have been associated with a higher probability of developing a hyper-autofluorescent ring on fundus autofluorescence imaging (PMID: 29550188).”

While the EYS gene was originally described in drosophila melanogaster, the EYS gene has apparently been lost in multiple lower mammalian species, therefore no murine data is available to support the gene-disease correlation. However, this gene-disease association is supported by multiple zebrafish model systems in which EYS gene knockout impairs electroretinogram recording, retinal structure and photoreceptor protein localization (PMIDs: 28378834, 30052645), consistent with a cone-rod dysfunction. Expression of EYS has also been validated in macaque retina (PMID: 27846257). Multiple cell culture models support the role of EYS in cellular ciliary structures, as EYS localizes to ciliary structures in vitro (PMIDs: 27846257, 33833316, 35410372).

In summary, EYS is definitively associated with autosomal recessive EYS-related retinopathy; while pathogenic variants are largely associated with retinitis pigmentosa (rod-cone dystrophy), other EYS-related phenotypes have also been described, including cone-rod dystrophy and macular dystrophy. The relationship with retinal dystrophy has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time, leading to a Definitive classification. This clinical validity classification was approved by the ClinGen Retina GCEP on November 2, 2022 (SOP v9).