Natural History of CNGA1-Associated Retinitis Pigmentosa in a Large Chinese Cohort Revealing an Optimal Intervention Window.

PURPOSE: To detail the natural history, clinical manifestations, and molecular characteristics of a large Chinese cohort of patients with CNGA1-associated retinitis pigmentosa (CNGA1-RP).

DESIGN: Single-center, retrospective case series.

PARTICIPANTS: A total of 58 Chinese patients with CNGA1-RP from 52 families were enrolled between 2011 and 2025.

METHODS: Longitudinal data were available for 20 individuals, with the longest follow-up of 11 years. All participants underwent comprehensive clinical evaluations and genetic analysis. The impact of age on best-corrected visual acuity (BCVA) and visual field (VF) was evaluated using restricted cubic spline (RCS) analysis. Retinal multimodal imaging was acquired, including optical coherence tomography (OCT), ultra-widefield (UWF) scanning laser ophthalmoscope (SLO) and UWF fundus autofluorescence (FAF). Moreover, electroretinogram (ERG) was performed.

MAIN OUTCOME MEASURES: Clinical symptoms, age-related changes in BCVA and VF, retinal multimodal imaging features, molecular characteristics.

RESULTS: Night blindness was the universal initial symptom, with most patients (88%) experiencing onset during childhood. BCVA remained stable (0.09 logMAR) until age of 30.7 years, followed by a progressive decline at 0.029 logMAR per year; by age of 72 years, 32% of patients had developed blindness (BCVA > 1.30 logMAR). VF impairment began in childhood and progressed to tunnel vision (VF ≤ 10°) at a median age of 39.4 years. A high degree of interocular symmetry was observed for both BCVA and VF. FAF imaging revealed a macular hyper-autofluorescent (hyperAF) ring in 73% of patients. Genetic analysis identified 14 novel pathogenic variants in CNGA1, and c.265delC was confirmed as a hotspot variant with an allele frequency of 72% in the Chinese population. Furthermore, homozygous carriers of this hotspot variant exhibited more severe phenotypes.

CONCLUSIONS: Our study characterized the natural history of CNGA1-RP and identified c.265delC as a hotspot variant in the Chinese population. Based on the quantitative data, VA loss in CNGA1-RP is late-onset and slow-progressing, whereas VF loss occurs earlier and more severely. The optimal window of intervention for CNGA1-RP in the Chinese population appears to be between the 3rd and 4th decade of life.