EYSmutation update: In silico assessment of 271 reported and 26 novel variants in patients with retinitis pigmentosa

Abstract

Mutations in Eyes shut homolog (EYS) are one of the most common causes of autosomal recessive (ar) retinitis pigmentosa (RP), a progressive blinding disorder. The exact function of the EYS protein and the pathogenic mechanisms underlying EYS-associated RP are still poorly understood, which hampers the interpretation of the causality of many EYS variants discovered to date. We collected all reported EYS variants present in 377 arRP index cases published before June 2017, and uploaded them in the Leiden Open Variation Database (www.LOVD.nl/EYS). We also describe 36 additional index cases, carrying 26 novel variants. Of the 297 unique EYS variants identified, almost half (n = 130) are predicted to result in premature truncation of the EYS protein. Classification of all variants using the American College of Medical Genetics and Genomics guidelines revealed that the predicted pathogenicity of these variants cover the complete spectrum ranging from likely benign to pathogenic, although especially missense variants largely fall in the category of uncertain significance. Besides the identification of likely benign alleles previously reported as being probably pathogenic, our comprehensive analysis underscores the need of functional assays to assess the causality of EYS variants, in order to improve molecular diagnostics and counseling of patients with EYS-associated RP.

Intra‐ and interspecies comparison of EYS transcripts highlights its characteristics in the eye

“…The 59 portion is fairly photoreceptor-specific based on the present study; however, it is suggested that the long EYS variants are essential for the maintenance of photoreceptors in humans from previous studies, which showed pathogenic mutations, particularly missense mutations that would have relatively little effect on the protein structure and are located at various positions of EYS gene (2,(19)(20)(21)(22)(23). This would also be true for zebrafish EYS.…”

Laminin G-like domains: dystroglycan-specific lectins

“…EYS contains five LG domains, the last three of which are predicted to have functional Ca 2+ binding sites (Figure 2B). Mutations in EYS are a common cause of autosomal recessive retinitis pigmentosa [62–64]. Over 100 unique missense variants have been detected, two of which affect a putative Ca 2+ ligand in LG4 (Asp2746).…”

Systematic detection of Mendelian and non-Mendelian variants associated with retinitis pigmentosa by genome-wide association study

“…Thus, the results are consistent with G843E being a hypomorphic ARRP allele and show that it can indeed sometimes cause mild retinal disease that may be overlooked without a thorough assessment. This may partly account for the gap between the known prevalence of RP and the allele frequency of G843E, complicating its interpretation in the past 11,13,32,33 . Assuming that G843E is an ARRP allele, the mutation would account for an additional 7.0% of Japanese cases of RP, which would increase the proportion of genetically solved cases by 26.8%, either as compound heterozygotes or homozygotes.…”