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

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.

Figure 1.. Example of Milder (A and B) and Severe (C and D) Forms of CLN3-Related Isolated Retinal Degeneration

A, Short-wavelength fundus autofluorescence perifoveal hyperautofluorescent annulus with macular edema in patient CIC09853 with genotype M2, M8, and M11. B, Spectral-domain optical coherence tomography (horizontal scan) of the same patient revealed cystoid maculopathy with a preserved ellipsoid zone. C, Short-wavelength fundus autofluorescence in patient CIC09088 with genotype M5 and M9. D, Spectral-domain optical coherence tomography widespread disruption of ellipsoid zone in the same patient.

Figure 2.. Spectrum of Variants in CLN3

Variants reported in retina-restricted disease (top) and in juvenile neuronal ceroid lipofuscinosis (JNCL; bottom). Most variants are clearly distinct. Blue indicates variants reported in both retina-restricted disease and JNCL. Red indicates novel variants. UTR indicates untranslated region.

Figure 3.. Phenotype–Genotype Correlations in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) and CLN3-Related Retina-Restricted Diseases

The patient harboring the p.(Arg405Trp) variant (in green) was recently reported to develop a late neurological involvement suggestive of JNCL. Blue indicates variants reported in both JNCL and retina-restricted disease. kb indicates kilobase pairs; Mb, megabase pairs; RD, retinal degeneration. ^aNovel variant.