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Abstract：
Introduction: Rett syndrome (RTT, MIM #312750) is a rare genetic disorder that leads to developmental regression and severe disability and is caused by pathogenic variants in the MECP2 gene. The diagnosis of RTT is based on clinical features and, depending on resources and access, on molecular confirmation. There is scarce information on molecular diagnosis from patients in Latin America, mostly due to limited availability and coverage of genomic testing. This pilot study aimed to implement genomic testing and characterize clinical and molecular findings in a group of Chilean patients with a clinical diagnosis of RTT. Methods: Twenty-eight patients with suspected RTT underwent characterization of phenotypic manifestations and molecular testing using Clinical Exome SolutionTM CES_V2 by SOPHiA Genetics. Data was analyzed using the commercial bioinformatics platform, SOPHiA DDMTM. A virtual panel of 34 genes, including MECP2 and other genes that are in the differential diagnosis of RTT, was used to prioritize initial analyses, followed by evaluation of the complete exome sequence data. Results: Twelve patients (42.8% of participants) had variants in MECP2, of which 11 (39.2%) were interpreted as pathogenic/likely pathogenic (P/LP), thus confirming the diagnosis of RTT in them. Eight additional patients (28.5%) harbored ten variants in nine other genes. Four of these variants were interpreted as P/LP (14.2%) (GRIN2B, MADD, TRPM3 and ZEB2) resulting in alternative neurodevelopmental diagnoses, and six were considered of uncertain significance. No evident candidate variant was found for eight patients. Discussion: This study allowed to reach a diagnosis in half of the participants. The diagnosis of RTT was confirmed in over a third of them, while others were found to have alternative neurodevelopmental disorders. Further evaluation is needed to identify the cause in those with negative or uncertain results. This information is useful for the patients, families, and clinicians to guide clinical management, even more so since the development of novel therapies for RTT. We also show the feasibility of implementing a step-wide approach to genomic testing in a setting with limited resources.
摘要：
简介：Rett综合征（RTT，MIM＃312750）是一种罕见的遗传性疾病，可导致发育退化和严重残疾，由MECP2基因的致病性变异引起。RTT的诊断基于临床特征,根据资源和访问，关于分子确认。拉丁美洲患者的分子诊断信息很少，主要是由于基因组测试的可用性和覆盖范围有限。这项初步研究旨在实施基因组测试，并在一组具有RTT临床诊断的智利患者中表征临床和分子发现。方法：28例疑似RTT患者通过SOPHiAGenetics使用临床外显子组溶液TMCES_V2进行表型表征和分子检测。使用商业生物信息学平台分析数据，SOPHIADDMTM。一个由34个基因组成的虚拟小组，包括MECP2和其他在RTT鉴别诊断中的基因，用于优先考虑初始分析，然后评估完整的外显子组序列数据。结果：12例患者（42.8％的参与者）有MECP2变异，其中11例（39.2％）被解释为致病性/可能致病性（P/LP）。从而证实了RTT在其中的诊断。另外8名患者（28.5％）在其他9个基因中携带10个变异。其中四个变体被解释为P/LP（14.2%）（GRIN2B，MADD,TRPM3和ZEB2）导致替代神经发育诊断，六个被认为具有不确定的意义。8例患者未发现明显的候选变异。讨论：这项研究允许一半的参与者得到诊断。超过三分之一的人证实了RTT的诊断，而其他人则被发现患有替代性神经发育障碍。需要进一步评估以确定结果为阴性或不确定的原因。这些信息对患者很有用，家庭,和临床医生指导临床管理，自RTT新疗法的开发以来，更是如此。我们还展示了在资源有限的环境中实施逐步方法进行基因组测试的可行性。
