학술논문
Retinal Phenotype of Patients With Isolated Retinal Degeneration Due to CLN3 Pathogenic Variants in a French Retinitis Pigmentosa Cohort.
Document Type
Academic Journal
Author
Smirnov VM; Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.; Université de Lille, Faculté de Médecine, Lille, France.; Exploration de la Vision et Neuro-Ophtalmologie, CHU de Lille, Lille, France.; Nassisi M; Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.; Solis Hernandez C; Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.; Méjécase C; Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.; Institute of Ophthalmology, University College London, London, United Kingdom.; El Shamieh S; Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.; Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon.; Condroyer C; Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.; Antonio A; Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.; Meunier I; Institute for Neurosciences Montpellier, INSERM U1051, University of Monpellier, Montpellier, France.; National Center for Rare Genetic Retinal Dystrophies, Hôpital Guy de Chauliac, Montpellier, France.; Andrieu C; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 1423, Paris, France.; Defoort-Dhellemmes S; Exploration de la Vision et Neuro-Ophtalmologie, CHU de Lille, Lille, France.; Mohand-Said S; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 1423, Paris, France.; Sahel JA; Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 1423, Paris, France.; Fondation Ophtalmologique Adolphe de Rothschild, Paris, France.; Académie des Sciences, Institut de France, Paris, France.; Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Audo I; Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.; Institute of Ophthalmology, University College London, London, United Kingdom.; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 1423, Paris, France.; Zeitz C; Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.
Source
Publisher: American Medical Association Country of Publication: United States NLM ID: 101589539 Publication Model: Print Cited Medium: Internet ISSN: 2168-6173 (Electronic) Linking ISSN: 21686165 NLM ISO Abbreviation: JAMA Ophthalmol Subsets: MEDLINE
Subject
Language
English
Abstract
Importance: Biallelic variants in CLN3 lead to a spectrum of diseases, ranging from severe neurodegeneration with retinal involvement (juvenile neuronal ceroid lipofuscinosis) to retina-restricted conditions.
Objective: To provide a detailed description of the retinal phenotype of patients with isolated retinal degeneration harboring biallelic CLN3 pathogenic variants and to attempt a phenotype-genotype correlation associated with this gene defect.
Design, Setting, and Participants: This retrospective cohort study included patients carrying biallelic CLN3 variants extracted from a cohort of patients with inherited retinal disorders (IRDs) investigated at the National Reference Center for Rare Ocular Diseases of the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts from December 2007 to August 2020. Data were analyzed from October 2019 to August 2020.
Main Outcome and Measures: Functional (best-corrected visual acuity, visual field, color vision, and full-field electroretinogram), morphological (multimodal retinal imaging), and clinical data from patients were collected and analyzed. Gene defect was identified by either next-generation sequencing or whole-exome sequencing and confirmed by Sanger sequencing, quantitative polymerase chain reaction, and cosegregation analysis.
Results: Of 1533 included patients, 843 (55.0%) were women and 690 (45.0%) were men. A total of 15 cases from 11 unrelated families harboring biallelic CLN3 variants were identified. All patients presented with nonsyndromic IRD. Two distinct patterns of retinal disease could be identified: a mild rod-cone degeneration of middle-age onset (n = 6; legal blindness threshold reached by 70s) and a severe retinal degeneration with early macular atrophic changes (n = 9; legal blindness threshold reached by 40s). Eleven distinct pathogenic variants were detected, of which 4 were novel. All but 1, p.(Arg405Trp), CLN3 point variants and their genotypic associations were clearly distinct between juvenile neuronal ceroid lipofuscinosis and retina-restricted disease. Mild and severe forms of retina-restricted CLN3-linked IRDs also had different genetic background.
Conclusions and Relevance: These findings suggest CLN3 should be included in next-generation sequencing panels when investigating patients with nonsyndromic rod-cone dystrophy. These results document phenotype-genotype correlations associated with specific variants in CLN3. However, caution seems warranted regarding the potential neurological outcome if a pathogenic variant in CLN3 is detected in a case of presumed isolated IRD for the onset of neurological symptoms could be delayed.
Objective: To provide a detailed description of the retinal phenotype of patients with isolated retinal degeneration harboring biallelic CLN3 pathogenic variants and to attempt a phenotype-genotype correlation associated with this gene defect.
Design, Setting, and Participants: This retrospective cohort study included patients carrying biallelic CLN3 variants extracted from a cohort of patients with inherited retinal disorders (IRDs) investigated at the National Reference Center for Rare Ocular Diseases of the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts from December 2007 to August 2020. Data were analyzed from October 2019 to August 2020.
Main Outcome and Measures: Functional (best-corrected visual acuity, visual field, color vision, and full-field electroretinogram), morphological (multimodal retinal imaging), and clinical data from patients were collected and analyzed. Gene defect was identified by either next-generation sequencing or whole-exome sequencing and confirmed by Sanger sequencing, quantitative polymerase chain reaction, and cosegregation analysis.
Results: Of 1533 included patients, 843 (55.0%) were women and 690 (45.0%) were men. A total of 15 cases from 11 unrelated families harboring biallelic CLN3 variants were identified. All patients presented with nonsyndromic IRD. Two distinct patterns of retinal disease could be identified: a mild rod-cone degeneration of middle-age onset (n = 6; legal blindness threshold reached by 70s) and a severe retinal degeneration with early macular atrophic changes (n = 9; legal blindness threshold reached by 40s). Eleven distinct pathogenic variants were detected, of which 4 were novel. All but 1, p.(Arg405Trp), CLN3 point variants and their genotypic associations were clearly distinct between juvenile neuronal ceroid lipofuscinosis and retina-restricted disease. Mild and severe forms of retina-restricted CLN3-linked IRDs also had different genetic background.
Conclusions and Relevance: These findings suggest CLN3 should be included in next-generation sequencing panels when investigating patients with nonsyndromic rod-cone dystrophy. These results document phenotype-genotype correlations associated with specific variants in CLN3. However, caution seems warranted regarding the potential neurological outcome if a pathogenic variant in CLN3 is detected in a case of presumed isolated IRD for the onset of neurological symptoms could be delayed.