Comprehensive Genotyping and Phenotyping Analysis of GUCY2D-Associated Rod- and Cone-Dominated Dystrophies

& BULL; PURPOSE: To describe the genetic and clinical spectrum of QUCY2D -associated retinopathies and to accurately establish their prevalence in a large cohort of patients. & BULL; DESIGN: Retrospective case series. & BULL; METHODS: Institutional study of 47 patients from 27 unrelated families with retinal dystrophies carrying disease-causing QUCY2D variants from the Fundacion Jimenez Diaz hospital dataset of 8000 patients. Patients underwent ophthalmological examination and molecular testing by Sanger or exome sequencing approaches. Statistical and principal component analyses were performed to determine genotype-phenotype correlations. & BULL; RESULTS: Four clinically different associated phenotypes were identified: 66.7% of families with cone/conerod dystrophy, 22.2% with Leber congenital amaurosis, 7.4% with early-onset retinitis pigmentosa, and 3.7% with congenital night blindness. Twenty-three diseasecausing QUCY2D variants were identified, including 6 novel variants. Biallelic variants accounted for 28% of patients, whereas most carried dominant alleles associated with cone/cone-rod dystrophy. The disease onset had statistically significant differences according to the functional variant effect. Patients carrying QUCY2D variants were projected into 3 subgroups by allelic combination, disease onset, and presence of nystagmus or night blindness. In contrast to patients with the most severe phenotype of Leber congenital amaurosis, 7 patients with biallelic QUCY2D had a later and milder rod form with night blindness in infancy as the first symptom. & BULL; CONCLUSIONS: This study represents the largest QUCY2D cohort in which 4 distinctly different phenotypes were identified, including rare intermediate presentations of rod-dominated retinopathies. We established that QUCY2D is linked to about 1% of approximately 3000 molecularly characterized families of our cohort. All of these findings are critical for defining cohorts for inclusion in future clinical trials. (Am J Ophthalmol 2023;254: 87-103. & COPY; 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NCND license ( http://creativecommons.org/licenses/by-ncnd/4.0/ ))

Automated summary

This study describes the genetic and clinical spectrum of QUCY2D-associated retinopathies and establishes their prevalence in a large cohort of patients. Four clinically different phenotypes were identified, and the different mutation types and disease onset differences associated with QUCY2D variants were determined. These findings are critical for defining cohorts for inclusion in future clinical trials.