Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.
Université de Lille, Faculté de Médecine, Lille, France.
JAMA Ophthalmol. 2021 Mar 1;139(3):278-291. doi: 10.1001/jamaophthalmol.2020.6089.
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.
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.
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.
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.
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.
CLN3 的双等位基因变异导致一系列疾病，从伴有视网膜受累的严重神经退行性疾病（青少年神经元蜡样脂褐质沉积症）到仅局限于视网膜的疾病。
详细描述携带双等位基因 CLN3 致病变异的孤立性视网膜变性患者的视网膜表型，并尝试与该基因缺陷相关的表型-基因型相关性。
设计、地点和参与者：本回顾性队列研究纳入了 2007 年 12 月至 2020 年 8 月期间在法国国家十五院眼科中心遗传性视网膜疾病（IRDs）国家参考中心接受检查的患者队列中提取的携带双等位基因 CLN3 变异的患者。数据于 2019 年 10 月至 2020 年 8 月进行分析。
收集并分析了患者的功能（最佳矫正视力、视野、色觉和全视野视网膜电图）、形态（多模态视网膜成像）和临床数据。通过下一代测序或外显子组测序鉴定基因缺陷，并通过 Sanger 测序、定量聚合酶链反应和连锁分析进行确认。
在纳入的 1533 例患者中，843 例（55.0%）为女性，690 例（45.0%）为男性。共发现 11 个无关家系的 15 例患者携带双等位基因 CLN3 变异。所有患者均表现为非综合征性 IRD。可识别出两种不同的视网膜疾病模式：一种是中年起病的轻度视杆-视锥变性（6 例；70 岁时达到法定失明阈值），另一种是早期黄斑萎缩的严重视网膜变性（9 例；40 岁时达到法定失明阈值）。共发现 11 种不同的致病性变异，其中 4 种为新变异。除 1 种（p.Arg405Trp）外，CLN3 点变异及其基因型相关性在青少年神经元蜡样脂褐质沉积症和仅局限于视网膜的疾病之间明显不同。CLN3 相关的轻度和重度局限于视网膜的 IRD 也具有不同的遗传背景。
这些发现提示在对非综合征性视杆-视锥营养不良患者进行下一代测序时，应将 CLN3 纳入其中。这些结果记录了与 CLN3 特定变异相关的表型-基因型相关性。然而，如果在假定的孤立性 IRD 中发现 CLN3 的致病性变异，由于神经症状的发作可能会延迟，因此对潜在的神经预后保持警惕似乎是合理的。
