Introduction

Biallelic pathogenic RPE65 variants are related to a spectrum of clinically overlapping inherited retinal dystrophies (IRD). Most affected individuals progress to severe disease, with 50% of patients becoming legally blind by 20 years of age. Deeper knowledge of the mutational spectrum and the phenotype-genotype correlation in RPE65-related IRD is needed.

Patients and methods

Forty-five affected subjects from 27 unrelated families with a clinical diagnosis of RPE65-related IRD were included. Clinical evaluation consisted of self-reported ophthalmological history and objective ophthalmological examination. Patients’ genotype was classified according to variant class (truncating or missense) or to variant location at different protein domains. The main phenotypic outcome measure was age at onset (AAO) of symptomatic disease and a Kaplan–Meier analysis of disease symptom event-free survival was performed.

Results

Twenty-nine different RPE65 variants were identified in our cohort, 7 of them novel. Patients carrying two missense alleles showed a later disease onset than those with 1 or 2 truncating variants (log-rank test p <0.05). While 60% of patients carrying a missense/missense genotype presented symptoms before or during the first year of life, almost all patients with at least 1 truncating allele (91%) had an AAO ≤1 year (p <0.05).

Conclusion

Our findings suggest an association between the type of RPE65 variant carried and AAO. These findings provide useful data on RPE65-associated IRD phenotypes and may help improve clinical and therapeutic management of these patients.

中文翻译：

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RPE65 相关的视网膜营养不良：45 名受影响患者的突变和表型谱

介绍

双等位基因致病性RPE65变异与一系列临床重叠的遗传性视网膜营养不良 (IRD) 相关。大多数受影响的个体会发展为严重疾病，50% 的患者在 20 岁时成为法定失明。需要更深入地了解RPE65相关 IRD中的突变谱和表型-基因型相关性。

患者和方法

包括来自 27 个无关家庭的 45 名临床诊断为RPE65相关 IRD 的受影响受试者。临床评估包括自我报告的眼科病史和客观的眼科检查。根据变异类别（截断或错义）或不同蛋白质结构域的变异位置对患者的基因型进行分类。主要的表型结果测量是有症状疾病的发病年龄 (AAO)，并对疾病症状无事件生存率进行 Kaplan-Meier 分析。

结果

在我们的队列中发现了29 种不同的RPE65变体，其中 7 种是新的。携带两个错义等位基因的患者比携带 1 或 2 个截短变异的患者发病晚（对数秩检验 p <0.05）。虽然 60% 的携带错义/错义基因型的患者在出生前或出生第一年期间出现症状，但几乎所有至少有 1 个截短等位基因的患者 (91%) 的 AAO ≤ 1 年 (p <0.05)。

结论

我们的研究结果表明携带的RPE65变体类型与 AAO之间存在关联。这些发现提供了有关RPE65相关 IRD 表型的有用数据，并可能有助于改善这些患者的临床和治疗管理。