Background and objective

Inherited retinal dystrophies (IRDs) are a major cause of childhood blindness. Timely diagnosis requires a high level of clinical suspicion from both neurologists and ophthalmologists and is increasingly important given recent advancements in gene therapy. We focused our study on genotype-phenotype associations in very early-onset forms of retinal dystrophy, the least well characterized and most challenging diagnostic subgroup.

Methods

From January 12, 2015 to March 31, 2017, we prospectively performed whole exome sequencing targeted on the phenotype of non-syndromic IRDs and phenotype characterization in a cohort of 68 children affected by very early-onset inherited retinal dystrophies, defined by the onset before five years of age. Phenotype parameters included age at onset, clinical presentation, ophthalmic evaluation, electrophysiological patterns and clinical course.

Results

A genetically confirmed diagnosis was achieved in 50 out of 60 (83%) families. The median age at onset was 4 months (<6 m in 70%, < 2 y in 82% of the cases). Clinical presentation was associated with visual loss and nystagmus in the majority of patients. Three (CNGB3, CNGA3 and CACNA1F) out of 22 genes considered pathogenic in the cohort, accounted for 51% of all IRD’s, all within the class of stationary IRDs.

Conclusions

This study reports on the largest cohort of very early-onset retinal dystrophies, including a description of electroretinography patterns. The electro-clinical phenotype coupled with genetic diagnosis provided additional clues for child neurologists dealing with low vision and nystagmus in infancy. A high level of clinical suspicion improves the diagnosis with important implications for the future of the affected child.

中文翻译：

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极早发性视网膜营养不良儿科患者的外显子组测序和电临床特征：一项队列研究

背景和目标

遗传性视网膜营养不良 (IRD) 是儿童失明的主要原因。及时诊断需要神经科医生和眼科医生的高度临床怀疑，并且鉴于基因治疗的最新进展，这一点变得越来越重要。我们将研究重点放在非常早发的视网膜营养不良形式中的基因型 - 表型关联，这是特征最少且最具挑战性的诊断亚组。

方法

从 2015 年 1 月 12 日到 2017 年 3 月 31 日，我们前瞻性地对一组 68 名受极早发性遗传性视网膜营养不良影响的儿童进行了针对非综合征 IRD 表型和表型表征的全外显子组测序，定义为之前发病五岁。表型参数包括发病年龄、临床表现、眼科评估、电生理模式和临床病程。

结果

在 60 个 (83%) 家庭中，有 50 个获得了基因确诊。发病的中位年龄为 4 个月（70% 的病例 < 6 m，82% 的病例 < 2 岁）。大多数患者的临床表现与视力丧失和眼球震颤有关。队列中被认为是致病基因的 22 个基因中的三个（CNGB3、CNGA3 和 CACNA1F）占所有 IRD 的 51%，均属于静止 IRD 类。

结论

这项研究报告了最大的极早发性视网膜营养不良队列，包括对视网膜电图模式的描述。电临床表型与基因诊断相结合，为处理婴儿期低视力和眼球震颤的儿童神经科医生提供了额外的线索。高度的临床怀疑可以改善诊断，对受影响儿童的未来产生重要影响。