The mutational and clinical spectrum of EYS-associated retinitis pigmentosa in an Eastern European and Northern Asian cohort: two recurrent founder alleles

Abstract

Purpose Biallelic EYS variants are one of the frequent causes of autosomal recessive inherited retinal disease worldwide, yet the EYS mutational landscape of Eastern European and Northern Asian populations has not been systematically described. We characterized the molecular and clinical spectrum of EYS-associated retinitis pigmentosa (RP) in this population. Methods Thirty-nine patients with confirmed biallelic EYS variants were selected from 500 patients enrolled in the prospective inherited retinal disease genotyping clinical trial (NCT03901391). All patients underwent whole exome sequencing with copy number/structural variant analysis and standardized ophthalmic phenotyping, including best corrected visual acuity (BCVA), slit lamp biomicroscopy, refractometry, perimetry, optical coherent tomography (OCT), fundus autofluorescence (FAF), ophthalmoscopy and electroretinogram (ERG). Results We identified 34 distinct EYS variants: 22 pathogenic, 8 likely pathogenic, and 4 variants of uncertain significance by American College of Medical Genetics (ACMG) criteria. Fifteen variants were novel, including eight structural deletions. Two recurrent alleles c.1155T>A (p.Cys385*) in 16 (20.3%) alleles, and c.8648_8655del (p.Thr2883Lysfs*4) in 15 (19.0%) alleles were the most frequent; together they accounted for 39.2% of alleles, with relatedness analysis supporting a shared founder origin. Median age of disease manifestation was 18 years and median BCVA 0.16 logMAR; worse acuity correlated with older age (rank correlation coefficient = 0.34, p = 0.035). Conclusion This first description of the EYS spectrum in an Eastern European and Northern Asian cohort expands the allelic diversity of the gene, provides a genotype-phenotype description and defines two population-specific founder alleles amenable to targeted screening and future treatment.