Phenotypic Distinctions Between EYS- and USH2A-Associated Retinitis Pigmentosa in an Asian Population

Abstract

Purpose: This study compares clinical characteristics of retinitis pigmentosa (RP) associated with mutations in the EYS and USH2A genes in a Southeast Asian cohort.

Methods: Prospective single-center study of families with EYS- or USH2A-associated RP seen at the Singapore National Eye Centre. Comprehensive ophthalmic evaluations, multimodal imaging, genetic testing, and longitudinal follow-up identified clinically useful differentiating features between the two genotypes.

Results: A total of 300 families with RP were enrolled, with EYS- and USH2A-associated RP, accounting for 24.7% of all probands and 50.7% of solved or likely solved cases. USH2A cases were predominantly nonsyndromic RP (75%). EYS-associated RP was more severe in functional and structural outcomes, and patients were more myopic than USH2A (SE -3.31 vs. -0.69; P < 0.0001). EYS RP displayed peripapillary nasal sparing on autofluorescence imaging more frequently than USH2A (57.6% vs. 26.7%; P = 0.006), whereas USH2A cases more often had a parafoveal ring (73.3% vs. 30.3%; P = 0.0002). Multiple logistic regression identified diagnostic features with 83.2% accuracy in distinguishing between EYS and USH2A, validated in a second unrelated clinical cohort.

Conclusions: EYS- and USH2A-associated RP have overlapping clinical presentations but can often be distinguished based on a constellation of phenotypic features including disease onset and severity, refractive error, and fundus autofluorescence. These diagnostic features may support a more effective diagnostic strategy for these common forms of RP.

Translational relevance: Distinct clinical features differentiating EYS- and USH2A-associated RP provide valuable diagnostic tools that may inform personalized management and facilitate targeted interventions in clinical practice.

Figure 1.

Composition of RP genotypes in the Singapore RP study cohort. A total of 300 unrelated RP probands were included. Cases with biallelic EYS or USH2A RP, biallelic EYS or USH2A RP wherein one or both alleles included the EYS C2139Y or USH2A C934W variant or were only a single EYS or USH2A variant was identified, are shown in exploded slices. The remaining RP cases without EYS or USH2A, both solved/others and unsolved, are also shown.

Figure 2.

Baseline clinical features of RP cases with EYS or USH2A. (A) Age at symptom onset and presentation; (B) BCVA; and (C) horizontal visual field diameter (°) on the V4e isopter on Goldmann kinetic perimetry are sown as scatter plots. Median values are shown as horizontal bars. EYS and USH2A groups were compared with Mann Whitney tests. Ns, not significant.

Figure 3.

Survival curves for EYS- and USH2A-associated RP clinical features. Visual acuity cutoffs of logMAR 0.5 (A) and 1.0 (B), visual field cutoffs of 60° (C) and 20° (D), ellipsoid band width of 15° (E) and 5° (F), and ffERG extinction for DA 0.01 (G), DA 10.0 (H), and LA 3.0 (I) are shown for both groups. Survival curves were compared using log-rank (Mantel Cox) tests for significance, with P values shown as insets.

Figure 4.

Comparisons in outcomes for EYS- and USH2A-associated RP, based in patient age and time elapsed since symptom onset. Presenting BCVA (A and B), horizontal visual field diameter (C and D), and horizontal EZ band length (E and F) are plotted against patient age or years elapsed since symptom onset. Linear regression (lin. reg.) was used to compare the two genotypes, with ANCOVA analysis comparing the regression lines. Significance of ANCOVA is shown as P values inset.

Figure 5.

Autofluorescence imaging distinguishes between EYS and USH2A RP. (A) Peripapillary nasal sparing was more prevalent among individuals with EYS (P = 0.0019) whereas a parafoveal ring was more prevalent among individuals with USH2A (P = 0.0002). (B) Illustrative cases for both features are shown, along with the EYS and USH2A genotypes identified for each case.

Figure 6.

Multiple logistic regression analysis incorporating age at symptom onset, presenting BCVA, spherical equivalent, peripapillary nasal sparing, and perifoveal ring or fundus AF, were used to distinguish between EYS and USH2A (A). Negative predictive power (NPP) and positive predictive power (PPP) are shown. (B) The predicted probabilities for EYS and USH2A cohorts are shown as violin plots, where median and quartiles are shown as horizontal bars.