Longitudinal Clinical Follow-up and Genetic Spectrum of Patients With Rod-Cone Dystrophy Associated With Mutations inPDE6AandPDE6B

Abstract

IMPORTANCE A precise phenotypic characterization of retinal dystrophies is needed for disease modeling as a basis for future therapeutic interventions. OBJECTIVE To compare genotype, phenotype, and structural changes in patients with rod-cone dystrophy (RCD) associated with mutations in PDE6A or PDE6B. DESIGN, SETTING, AND PARTICIPANTS In a retrospective cohort study conducted in Paris, France, from January 2007 to September 2017, 54 patients from a cohort of 1095 index patients with RCD underwent clinical examination, including personal and familial history, best-corrected visual acuity (BCVA), color vision, slitlamp examination, full-field electroretinography, kinetic visual fields (VFs), retinophotography, optical coherence tomography, near-infrared fundus autofluorescence, and short-wavelength fundus autofluorescence imaging. Genotyping was performed using microarray analysis, targeted next-generation sequencing, and Sanger sequencing validation with familial segregation when possible. Data were analyzed from September 1, 2017, to February 1, 2018. Clinical variables were subsequently analyzed in 2018. MAIN OUTCOMES AND MEASURES Phenotype and genotype comparison of patients carrying mutations in PDE6A or PDE6B. RESULTS Of the 54 patients included in the study, 19 patients of 17 families (11 women [58%]; mean [SD] age at diagnosis, 14.83 [10.63] years) carried pathogenic mutations in PDE6A, and 35 patients of 26 families (17 women [49%]; mean [SD] age at diagnosis, 21.10 [11.56] years) had mutations in PDE6B, accounting for prevalences of 1.6% and 2.4%, respectively. Among 49 identified genetic variants, 14 in PDE6A and 15 in PDE6B were novel. Overall, phenotypic analysis revealed no substantial differences between the 2 groups except for night blindness as a presenting symptom that was noted to be more prevalent in the PDE6A than PDE6B group (80% vs 37%, respectively; P = .005). The mean binocular BCVA and VF decrease over time (measured as mean individual slopes coefficients) was comparable between patients with PDE6A and PDE6B mutations: 0.04 (0.12) vs 0.02 (0.05) for BCVA (P = .89) and 14.33 (7.12) vs 13.27 (6.77) for VF (P = .48). CONCLUSIONS AND RELEVANCE Mutations in PDE6A and PDE6B accounted for 1.6% and 2.4%, respectively, in a cohort of French patients with RCD. The functional and structural findings reported may constitute the basis of disease modeling that might be used for better prognostic estimation and candidate selection for photoreceptor therapeutic rescue.

Comparative Analysis of Functional and Structural Decline in Retinitis Pigmentosas

“…Nevertheless, this ellipsoid has been observed to progressively evolve into a uniformly round shape, which occurs due to a difference in the rate of one ring diameter's constriction compared to that of the other diameter. In our study, we found a faster rate of progression for the horizontal diameter in comparison to the vertical (Table 5), which is in accordance with the findings in the literature [26,27]. Thus, it is expected that the horizontal diameter would have a better correlation with ERG as opposed to the vertical diameter of the hyperfluorescent ring, due to the faster progression of the former.…”

Clinical characteristics and disease progression of retinitis pigmentosa associated with PDE6B mutations in Korean patients

“…The mean age at diagnosis was 27.5 years (range, 11-60 years) in our cohort. This is similar to that reported in a previous study of RP associated with mutations in the PDE6 gene family (21.0 years; range, 3-45 years) 12 ; however, it is much lower than the mean age at diagnosis reported in a study examining all types of RP in patients of Korean ethnicity (44.8 years; range, 0-95 years) 13 . Considering the age of disease onset, the patients with PDE6B variants in our study experienced their first ocular symptoms at a median age of 10.0 years; this is relatively early compared to the median age of onset reported in a previous study of RP associated with other causative genes (29 years; range, 4-77 years) 14 .…”

“…Among the PDE6B variants identified in this study, c.1669C > T was the most common, followed by c.1604T > A. Both variants have been commonly reported in a database of PDE6B mutations 24 , but the frequency of variants in our study was notably different to that observed in European patients 12 . Correlating characteristic phenotypes with PDE6B variants, we found that CME is frequently found in patients with the c.1669C > T variant.…”

“…The median age at examination was 40.0 years (range, . The mean follow-up duration was 3.1 years (range, [1][2][3][4][5][6][7][8][9][10][11][12]. According to their clinical history, 13 of 15 patients (86.7%) experienced night blindness as their first ocular symptom at a median age of 10.0 years (range, 5-47 years) and 9 of 15 patients (60.0%) were less than 10 years old at symptom onset.…”

Patient-Specific Retinal Organoids Recapitulate Disease Features of Late-Onset Retinitis Pigmentosa

“…Mutations in the gene encoding the beta subunit of rod cGMP-phosphodiesterase type 6 (PDE6B) account for 4 to 5% of autosomal recessive RP (Danciger et al, 1995). Recently, PDE6B mutation was identified as disease-causing gene in 2.4% patients from a large cohort of 1095 patients with RP (Khateb et al, 2019). Prevalent mouse models harboring Pde6b mutations, rd1, and rd10 have been widely used for deciphering pathogenesis and examining novel therapeutics for RP (Bowes et al, 1990; Barhoum et al, 2008).…”