Samer Khateb1,2,3, Marco Nassisi1,2, Kinga M Bujakowska1,4, Cécile Méjécase1, Christel Condroyer1, Aline Antonio1,2, Marine Foussard1, Vanessa Démontant1, Saddek Mohand-Saïd1,2, José-Alain Sahel1,2,5,6,7, Christina Zeitz1, Isabelle Audo1,2,8. 1. Sorbonne Université, Institut national de la santé et de la recherche médicale, Centre national de la recherche scientifique, Institut de la Vision, Paris, France. 2. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, DHU Sight Restore, Inserm-Direction Générale de l'Offre de Soins, CIC1423, Paris, France. 3. Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 4. Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. 5. Fondation Ophtalmologique Adolphe de Rothschild, Paris, France. 6. Department of Ophthalmology, The University of Pittsburgh Medical School, Pittsburgh, Pennsylvania. 7. Académie des Sciences-Institut de France, Paris, France. 8. Institute of Ophthalmology, University College London, London, United Kingdom.
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.
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.
Authors: Anthony G Robson; Adnan Tufail; Fred Fitzke; Alan C Bird; Anthony T Moore; Graham E Holder; Andrew R Webster Journal: Retina Date: 2011-09 Impact factor: 4.256
Authors: Marco Nassisi; Vasily M Smirnov; Cyntia Solis Hernandez; Saddek Mohand-Saïd; Christel Condroyer; Aline Antonio; Laura Kühlewein; Melanie Kempf; Susanne Kohl; Bernd Wissinger; Fadi Nasser; Sara D Ragi; Nan-Kai Wang; Janet R Sparrow; Vivienne C Greenstein; Stylianos Michalakis; Omar A Mahroo; Rola Ba-Abbad; Michel Michaelides; Andrew R Webster; Simona Degli Esposti; Brooke Saffren; Jenina Capasso; Alex Levin; William W Hauswirth; Claire-Marie Dhaenens; Sabine Defoort-Dhellemmes; Stephen H Tsang; Eberhart Zrenner; Jose-Alain Sahel; Simon M Petersen-Jones; Christina Zeitz; Isabelle Audo Journal: Hum Mutat Date: 2021-05-16 Impact factor: 4.700
Authors: Thiago Cabral; Jose Ronaldo Lima de Carvalho; Joonpyo Kim; Jin Kyun Oh; Sarah R Levi; Karen Sophia Park; Jimmy K Duong; Junhyung Park; Katherine Boudreault; Rubens Belfort; Stephen H Tsang Journal: Int J Mol Sci Date: 2020-04-15 Impact factor: 5.923