Retinal Phenotype of Patients With Isolated Retinal Degeneration Due to<i>CLN3</i>Pathogenic Variants in a French Retinitis Pigmentosa Cohort

Abstract

<h3>Importance</h3> Biallelic variants in<i>CLN3</i>lead to a spectrum of diseases, ranging from severe neurodegeneration with retinal involvement (juvenile neuronal ceroid lipofuscinosis) to retina-restricted conditions. <h3>Objective</h3> To provide a detailed description of the retinal phenotype of patients with isolated retinal degeneration harboring biallelic<i>CLN3</i>pathogenic variants and to attempt a phenotype–genotype correlation associated with this gene defect. <h3>Design, Setting, and Participants</h3> This retrospective cohort study included patients carrying biallelic<i>CLN3</i>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. <h3>Main Outcome and Measures</h3> 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. <h3>Results</h3> 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<i>CLN3</i>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),<i>CLN3</i>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<i>CLN3</i>-linked IRDs also had different genetic background. <h3>Conclusions and Relevance</h3> These findings suggest<i>CLN3</i>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<i>CLN3</i>. However, caution seems warranted regarding the potential neurological outcome if a pathogenic variant in<i>CLN3</i>is detected in a case of presumed isolated IRD for the onset of neurological symptoms could be delayed.