Genotype-phenotype correlations in patients with Usher syndrome type 2 harboring mutations in USH2A and ADGRV1

Abstract

Purpose : Mutations in USH2A are the most common cause of syndromic and non-syndromic retinitis pigmentosa (RP). Mutations in ADGRV1 (GPR98) are an infrequent cause of syndromic RP and the clinical presentation is less well known. The purpose of the study was to compare disease severity in a cohort of patients harboring mutations in USH2A and ADGRV1.

Methods : Study included patients with Usher syndrome type 2 and biallelic mutations in USH2A (N=188, median age 45 years) or ADGRV1 (N=17, median age 54 years). The onset of nyctalopia was determined from the hospital records. The degree of macular involvement was evaluated in 109 patients using fundus autofluorescence (FAF) and optical coherence tomography (OCT). The right eye was studied except where poor image quality precluded measurements. The diameter of the hyperautofluorescent ring was measured on FAF if present, or considered zero if there was central hyperautofluorescent patch or atrophy. The central retinal thickness (CRT) of 1 mm radius was measured on the OCT scan.

Results : The median age of onset of USH2A and ADGRV1 patients was 18 vs. 30 years (p>0.05, Mann Whitney U test). FAF patterns were qualitatively similar among the two groups. When adjusted for age, there was no significant difference in ring diameter, while ADGRV1 patients had significantly higher CRT (Multiple regression a analysis, p<0.001). Those USH2A patients with at least one missense variant (84/188) had significantly later median onset than those without (20 vs. 15 years, respectively; Mann Whitney U test, p<0.005). There was no significant difference in ring diameter or CRT among the two subgroups, when adjusted for age (Multiple regression analysis, p>0.05).

Conclusions : Results indicate milder retinal disease in Usher type 2 patients harboring ADGRV1 mutations although significance was reached only for CRT. Syndromic USH2A patients with missense variants were more likely to have a later disease onset than those with other variants however the degree of macular involvement determined objectively did not differ significantly.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.