探讨MECP2基因变异患儿的临床特征、遗传学病因及随访结果。

选择2017年10月至2025年3月于安徽医科大学第一附属医院分子诊断确诊的15例MECP2基因变异患儿为研究对象，为来自无亲缘关系的独立家系，按确诊时间将其命名为先证者1~15。采用单中心回顾性队列分析方法，收集其一般临床资料、临床表型、辅助检查结果、治疗及随访结果资料。采用全外显子组测序(WES)检测患儿及其父母的基因变异，并通过Sanger测序进行家系验证(评估遗传变异来源与疾病共分离)。依据美国医学遗传学与基因组学学会/分子病理学学会(ACMG/AMP)制定的《遗传变异分类标准与指南》(以下简称为"ACMG指南")，对检出的MECP2基因变异进行致病性分级，并结合Rett综合征(RTT)患儿诊断标准及美国国家神经疾病和卒中研究所2018年发布的RTT临床分期标准进行综合评估。本研究经安徽医科大学第一附属医院医学伦理委员会审核批准(批件号：PJ-2024-12-62)，研究对象法定监护人均签署临床研究知情同意书。

本研究先证者1~15的临床特点与检查结果如下。①先证者1、4~8、11~15为女性(11例)，确诊年龄为1岁3个月至5岁；先证者2、3、9、10为男性(4例)，确诊年龄为9个月龄至7岁1个月。先证者1、3~7、10~12、15(8例)符合典型RTT诊断，先证者2、8、13为非典型RTT，2例未达RTT诊断阈值[先证者9被诊断为全面性发育迟缓伴倒退，先证者14为孤独症谱系障碍(ASD)]。8例典型RTT患儿均存在发育倒退、手的精细运动功能及语言能力丧失，并伴手部刻板动作；其中，男性患儿的临床表型异质性较女性显著。②初诊时，先证者1、5~6、10、13、15合并癫痫，先证者7、11无癫痫发作(仅脑电图异常)，先证者2~4、8~9、12、14脑电图结果正常(先证者2、4、12在病程中出现癫痫发作和脑电图痫样放电)；先证者8、15头颅MRI检查结果异常者，其余初诊时头颅MRI未见明显异常。③WES结果显示，先证者4~5、7、12~13为MECP2基因无义变异，先证者1、6、10、14为错义变异，先证者2~3、8、15为移码/剪接位点变异，先证者9、11为拷贝数变异(CNV)患儿。对先证者1、3~8、11~15(12例)及其家系成员的Sanger测序验证结果示，父母均未携带该变异，上述12例先证者的MECP2基因变异均为新发变异，先证者2、9~10遗传学病因为母系遗传。依据ACMG指南，上述MECP2基因变异，均被评定为致病(P)或可能致病(LP)变异，其中先证者2移码变异(p. L383Profs*5)为本研究首次报道。④先证者1~8、10~13、15(13例)被初诊为RTT时，按照美国国家神经疾病与卒中研究院(NINDS)临床分期标准，被分为Ⅱ期者为10例，Ⅰ期者为3例。对其随访2~96个月的结果显示，先证者2~3、10死亡，均为RTT男性患儿，而且均表现为病情进展迅速并伴严重并发症。最终诊断癫痫的9例先证者中，先证者1、2、10为难治性癫痫，预后不良，先证者4~6、13癫痫控制良好，先证者12、15癫痫经短时随访控制可。另外6例MECP2基因变异先证者截至发稿尚未合并癫痫。

MECP2基因变异所致RTT患儿的临床表型异质性较大，女性患儿以典型RTT为主要临床表型，男性病情进展快，并且预后较差，表现为发育迟缓或严重致死性脑病，癫痫控制情况与认知、运动功能保留程度存在一定相关性。

To investigate the clinical characteristics, genetic features, and follow-up outcomes of children with MECP2 gene mutations.

A retrospective analysis was conducted on the clinical data of 15 children with MECP2 gene mutations diagnosed by molecular testing at the First Affiliated Hospital of Anhui Medical University from October 2017 to March 2025. Data collected included general information, clinical phenotypes, auxiliary examination results, treatment, and follow-up records. Whole-exome sequencing (WES) was performed to detect gene mutations in the children and their parents, with Sanger sequencing for verification and pedigree co-segregation analysis. Pathogenicity grading was performed according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, combined with RTT diagnostic criteria and clinical staging for comprehensive evaluation. This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Anhui Medical University (Approval No. PJ-2024-12-62), and all legal guardians of the subjects provided written informed consent.

① Among the 15 children, 11 were female and 4 were male. Ten cases met the diagnostic criteria for typical RTT, three were atypical RTT, and two did not meet the RTT diagnostic threshold (one case with pervasive developmental delay and regression, and one with autism spectrum disorder). All typical RTT cases exhibited developmental regression, loss of hand function and language ability, and associated with hand stereotyped movements. Male children showed significant clinical phenotypic heterogeneity. ②At initial diagnosis, six cases had coexisting epilepsy, two had only abnormal electroencephalogram (EEG), and three of the seven with normal EEG developed epilepsy during the course of the disease. At initial diagnosis, 2 cases exhibited abnormal cranial MRI findings. Among the 15 pediatric patients, 5 cases had nonsense mutations, 4 cases had missense mutations, 4 cases had frameshift/splicing site mutations, and 2 cases had copy number variations (CNV). Of these, 12 cases presented with novel mutations, and 3 cases were maternally inherited. According to the ACMG/AMP guidelines, all identified mutations were classified as pathogenic (L) or potentially pathogenic (LP), including a frameshift mutation (p.L383Profs*5) reported for the first time in this study. Among the 13 RTT patients, 10 were in stage Ⅱ at initial diagnosis, and 3 were in stage Ⅰ. Follow-up ranged from 2 to 96 months. Three male patients died, all exhibiting rapid disease progression with severe complications. The disease progression in 9 RTT patients was observed over time, with 1 case showing no progression and 2 cases with stable conditions (non-RTT). Among the 9 cases finally diagnosed with epilepsy, 3 cases were refractory epilepsy with poor prognosis, 4 cases had well-controlled epilepsy, and 2 cases had controlled epilepsy after short-term follow-up.

MECP2 gene mutations are associated with significant clinical phenotypic heterogeneity. Female patients predominantly present with classic RTT phenotypes, while male patients exhibit rapid disease progression and poor prognosis, manifesting as developmental delay or severe fatal encephalopathy. Epilepsy control is correlated with the degree of functional preservation.