Rim, J.H., Lee, S.T., Gee, H.Y., et al.
综合征 小儿 眼球
摘要：重要性：小儿眼球震颤综合征（INS）是一组具有遗传和临床异质性的疾病，对INS的遗传和临床诊断提出了挑战。目的：旨在评估新一代测序（NGS）基因组数据和表型数据的对加强INS的明确诊断的准确性。设计，设置，和研究对象：进行了一项单中心回顾性病例系列研究，对48名不相关的，连续的INS患者进行了研究，这些患者有或没有相关的眼部或全身状况，且在2015年6月1日至2017年1月31日期间接受基因检测。使用包括113个与INS相关的基因（n = 47）或包含与已知人表型（n = 1）相关的4813个基因的TruSight One测序板的靶标组进行分析。根据美国医学遗传学和基因组学指南，对变体进行深入的临床评估，并对其进行最终的分类。如果可行的话，患者接受详细的眼科检查，包括视网膜电图检查和光学相干断层扫描。主要预后指标：靶向NGS检测的诊断率。结果：48例患者中（女性21例，男性27例，基因检测时的平均[SD]年龄为9.2 [10.3]岁），8人有眼球震颤家族史，40人是单纯性。所有患者属于单一种族（韩国）。 48名患者中有28名患者发现了极有可能是致病因素的遗传变异，对应的分子诊断率为58.3％（95％CI，44.4％-72.2％）。 FRMD7，GPR143和PAX6突变似乎是家族性INS的主要遗传原因。根据NGS检测结果，共有10名患者（21％）被重新分类为不同的诊断，从而实现准确的临床治疗。结果和意义：由于诊断检测法，如电子视网膜照相术和光学相干断层扫描，不容易适用于婴幼儿，这些发现提示NGS是区分INS原因的准确诊断工具。在儿童早期，一种标准化，逐步的，基于团队方法下准确地应用NGS不仅有助于早期分子诊断，而且还可以改善INS患者的个性化治疗。
Importance:Infantile nystagmus syndrome (INS) is a group of disorders presenting with genetic and clinical heterogeneities that have challenged the genetic and clinical diagnoses of INS. Precise molecular diagnosis in early infancy may result in more accurate genetic counseling and improved patient management.Objective:To assess the accuracy of genomic data from next-generation sequencing (NGS) and phenotypic data to enhance the definitive diagnosis of INS.Design, Setting, and Participants:A single-center retrospective case series was conducted in 48 unrelated, consecutive patients with INS, with or without associated ocular or systemic conditions, who underwent genetic testing between June 1, 2015, and January 31, 2017. Next-generation sequencing analysis was performed using a target panel that included 113 genes associated with INS (n = 47) or a TruSight One sequencing panel that included 4813 genes associated with known human phenotypes (n = 1). Variants were filtered and prioritized by in-depth clinical review, and finally classified according to the American College of Medical Genetics and Genomics guidelines. Patients underwent a detailed ophthalmic examination, including electroretinography and optical coherence tomography, if feasible.Main Outcomes and Measures:Diagnostic yield of targeted NGS testing.Results:Among the 48 patients (21 female and 27 male; mean [SD] age at genetic testing, 9.2 [10.3] years), 8 had a family history of nystagmus and 40 were simplex. All patients were of a single ethnicity (Korean). Genetic variants that were highly likely to be causative were identified in 28 of the 48 patients, corresponding to a molecular diagnostic yield of 58.3% (95% CI, 44.4%-72.2%). FRMD7, GPR143, and PAX6 mutations appeared to be the major genetic causes of familial INS. A total of 10 patients (21%) were reclassified to a different diagnosis based on results of NGS testing, enabling accurate clinical management.Conclusions and Relevance:These findings suggest that NGS is an accurate diagnostic tool to differentiate causes of INS because diagnostic tests, such as electroretinography and optical coherence tomography, are not easily applicable in young infants. Accurate application of NGS using a standardized, stepwise, team-based approach in early childhood not only facilitated early molecular diagnosis but also led to improved personalized management in patients with INS.