Extending the Spectrum of EYS-Associated Retinal Disease to Macular Dystrophy

Laurence H M Pierrache, Muriël Messchaert, Alberta A H J Thiadens, Lonneke Haer-Wigman, Yvonne de Jong-Hesse, Wendy A G van Zelst-Stams, Rob W J Collin, Caroline C W Klaver, L Ingeborgh van den Born

Research output: Contribution to journalArticleResearchpeer-review


Purpose: To assess the phenotypic variability and natural course of inherited retinal diseases (IRDs) caused by EYS mutations.

Methods: Multiethnic cohort study (N = 30) with biallelic EYS variants from a clinical IRD database (retinitis pigmentosa [RP], N = 27; cone-rod dystrophy [CRD], N = 1; and macular dystrophy, N = 2). In vitro minigene splice assay was performed to determine the effect on EYS pre-mRNA splicing of the c.1299+5_1299+8del variant in macular dystrophy patients.

Results: We found 27 different EYS variants in RP patients and 7 were novel. The rate of visual field loss of the V4e isopter area was -0.84 ± 0.44 ln(deg2) per year, and the rate of visual acuity loss was 0.75 Early Treatment Diabetic Retinopathy Study letters per year. Ellipsoid zone width was correlated with area of the hyperautofluorescent ring, with rs = 0.78 and P < 0.001. Rate of decline in ellipsoid zone width was -57 ± 17 μm per year (P < 0.01) (n = 14) or -3.69% ± 0.51% from baseline per year (P < 0.001). An isolated CRD patient carried a homozygous EYS variant (c.9405T>A), previously identified in RP patients. Two siblings with macular dystrophy carried compound heterozygous EYS variants: c.1299+5_1299+8del and c.6050G>T. The former was novel and shown to result in skipping of exon 8, and the latter was a known RP variant.

Conclusions: We report on EYS-associated macular dystrophy, extending the spectrum of EYS-associated IRDs. We observed heterogeneity between RP patients in age of onset and disease progression. Identical EYS variants were found in cases with RP, CRD, and macular dystrophy. Screening for EYS variants in CRD and macular dystrophy patients might increase the diagnostic yield in previously unsolved cases.

Original languageEnglish
Pages (from-to)2049-2063
Number of pages15
JournalInvestigative ophthalmology & visual science
Issue number6
Publication statusPublished - 1 May 2019


  • Adult
  • Aged
  • Aged, 80 and over
  • DNA Mutational Analysis
  • Electroretinography
  • Eye Proteins/genetics
  • Female
  • Homozygote
  • Humans
  • Macular Degeneration/diagnosis
  • Male
  • Middle Aged
  • Mutation
  • Pedigree
  • Phenotype
  • RNA, Messenger/genetics
  • Retina/metabolism
  • Retinitis Pigmentosa/diagnosis
  • Tomography, Optical Coherence
  • Visual Acuity
  • Young Adult


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