目的

探讨Rubinstein-Taybi综合征（RSTS）先证者的临床特征和遗传学特点。

方法

选择2021年6月至2023年1月于西安市儿童医院就诊的3例RSTS先证者（先证者1～3）为研究对象。收集先证者1～3及其家庭成员的临床资料，采用全外显子组测序（WES）分析先证者1～3的致病基因变异，并且对候选基因变异位点进行Sanger测序、实时荧光定量聚合酶链反应（RTqPCR）验证及蛋白三维结构预测。检索国内外数据库中CREBBP 基因变异所致RSTS的相关临床研究文献纳入研究的RSTS患儿，对包括本研究先证者1～3的临床特点和基因变异情况进行总结。本研究遵循的程序符合西安市儿童医院伦理委员会制定的标准，并获得该伦理委员会批准（伦理委员会批号：20220019）。本研究纳入的先证者1～3监护人对本研究知情同意，并签署临床研究知情同意书。

结果

先证者1～3均具有RSTS患儿典型特征，即典型异常面容、宽拇指/脚趾畸形，轻、中度智力障碍或发育迟缓。基因分析结果显示，先证者1携带CREBBP 基因第3～19号外显子重复变异和GJB2 基因c.109G＞A（p.Val37Ile）纯合变异。先证者2、3分别携带CREBBP 基因c.5384G＞T（p.Cys1795Phe）和c.1409T＞A（p.Leu470*）新发杂合变异。上述先证者1～3的CREBBP 基因变异在人类基因突变数据库（HGMD）及Clin Var数据库均未见报道。结合先证者1～3的临床表型和基因分析结果，均将其判断为CREBBP 基因变异所致RSTS。

结论

RSTS为神经发育障碍性疾病，以CREBBP 基因突变所致的RSTS 1型最常见，患儿主要临床特征为特异性颅面畸形、宽拇指/脚趾畸形、智力障碍。对RSTS患者的早期识别并开展WES，可为临床诊断和后续妊娠的遗传学诊断提供依据。

Objective

To investigate clinical features and genetic variation characteristics of three probands with Rubinstein-Taybi syndrome （RSTS）.

Methods

From June 2021 to January 2023，three RSTS probands （probands 1-3）in Xi'an Children's Hospital were selected into this study.The clinical data of 3 probands and their family members were collected.The pathogenic genes of probands were analyzed by whole exon sequencing （WES），and the suspicious gene mutations were verified by Sanger sequencing，real time quantitative polymerase chain reaction （RT-qPCR）and the three-dimensional structure prediction of proteins.The related literature of RSTS caused by mutation of CREBBP gene in domestic and foreign databases was searched，and the clinical characteristics and gene variation of 3 probands were analyzed.The procedure followed in this study conforms to the standards formulated by the Ethics Committee of Xi'an Children's Hospital and has been approved by the Ethics Committee （Approval No，20220019）.Informed consents were obtained from all guardians of the proband of RSTS.

Results

Three probands （probands 1-3）had the typical characteristics of RSTS，namely，typical abnormal face，wide thumb/toe deformity，mild to moderate mental retardation or developmental retardation.Gene analysis showed that proband 1 carried repeated mutation of exon 3-19 of CREBBP gene and homozygous mutation of GJB2 gene c.109G＞A（p.Val37Ile）.Proband 2 and proband 3 carried new heterozygous variations of CREBBP gene c.5384G＞T（p.Cys1795Phe）and c.1409T＞A（p.Leu470*），respectively.These mutations had not been reported in HGMD and Clin Var databases.Combined with the clinical phenotype and gene analysis results of the probands，the three probands were caused by CREBBP gene mutation.

Conclusions

RSTS is a neurodevelopmental disorder，with type 1 of RSTS being the most common form，caused by mutations in the CREBBP gene.Its main features include distinctive facial deformities，enlarged thumbs and toes deformity，and intellectual impairment.Early detection through clinical assessment and WES can provide a molecular basis for diagnosis and aid in prenatal diagnosis for future pregnancies.