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Abstract：
Background: Infantile nystagmus syndrome (INS) is a genetically heterogeneous disorder. Identifying genetic causes of INS would help clinicians to facilitate clinical diagnosis and provide appropriate treatment. The aim of this study was to determine the diagnostic utility of targeted next-generation sequencing (NGS) for INS.Materials and methods: We recruited 37 patients who were referred to the Neuro-ophthalmology clinics for evaluations of INS. NGS was performed using a targeted panel that included 98 candidate genes associated with INS. We identified pathogenic variants according to guidelines of the American College of Medical Genetics and Genomics. We also calculated the sensitivity and specificity of each clinical sign to assess the diagnostic yield of our gene panel.Results: After variant filtering, annotation, and interpretation, the potential pathogenic variants were detected in 13 of the 37 patients, achieving a molecular diagnostic rate of 35%. The identified genes were PAX6 (n = 4), FRMD7 (n = 4), GPR143 (n = 2), CACNA1F (n = 1), CNGA3 (n = 1) and GUCY2D (n = 1). In approximately 30% (n = 4) of the patients, the initial clinical diagnosis was revised after a molecular diagnosis was performed. The presence of a family history had the highest predictive power for a molecular diagnosis (sensitivity = 61.5%, specificity = 91.7%), and the sensitivity increased when the family history was considered together with one of two clinical signs such as pendular nystagmus waveforms or anterior segment dysgenesis.Conclusions: Our study shows that targeted NGS can be useful to determine a molecular diagnosis for patients with INS. Targeted NGS also helps to confirm a clinical diagnosis in atypical phenotypes or unresolved cases.
摘要：
背景：婴儿眼震综合征（INS）是一种遗传异质性疾病。确定INS的遗传原因将有助于临床医生促进临床诊断并提供适当的治疗。这项研究的目的是确定针对INS的靶向下一代测序（NGS）的诊断实用性。材料和方法：我们招募了37例患者，他们被转诊到神经眼科诊所进行INS评估。使用包括与INS相关的98个候选基因的靶向组进行NGS。我们根据美国医学遗传学和基因组学学院的指南鉴定了致病变异。我们还计算了每个临床体征的敏感性和特异性，以评估我们基因组的诊断产量。结果：变异过滤后，注释,和解释，在37例患者中有13例检测到潜在的致病变异，分子诊断率达到35%。鉴定的基因是PAX6（n=4），FRMD7（n=4），GPR143（n=2），CACNA1F（n=1），CNGA3(n=1)和GUCY2D(n=1)。在大约30％（n=4）的患者中，在进行分子诊断后,对初始临床诊断进行了修订.家族史的存在对分子诊断的预测能力最高(灵敏度=61.5%,特异性=91.7%)，当将家族史与两种临床体征之一（例如摆动性眼球震颤波形或眼前节发育不全）一起考虑时，敏感性增加。结论：我们的研究表明，靶向NGS可用于确定INS患者的分子诊断。靶向NGS还有助于确认非典型表型或未解决病例的临床诊断。
