Rubinstein-Taybi Syndrome

Rubinstein-Taybi Syndrome (RSTS) is a rare congenital disease with distinctive facial features, broad thumbs and halluces, and developmental delay. RSTS is caused by de novo genetic alterations in CREBBP and the homologous EP300 genes. In this study, we established a genetic diagnosis protocol by integrating multiplex ligation-dependent probe amplification (MLPA) and whole exome sequencing (WES). In total, five patients clinically diagnosed of RSTS were enrolled for genetic testing. Germline DNA was extracted from the peripheral blood of the patients and their families. One patient (Case 1) was identified to harbor a large heterozygous deletion in 16p13.3 region, spanning the CREBBP gene. Three patients (Cases 2-4) harbored different CREBBP variants (c.2608C>T:p.Gln870Ter, c.4404_4405del:p.Thr1468fs, c.3649C>T:p.Gln1217Ter). No causative variants were identified for the fifth RSTS patient (Case 5). Here, we propose a molecular diagnostic protocol which identified causative genetic alterations in 4/5 of the patients yielding a molecular diagnostic rate of 80%. Given the rarity of the disease, more research is indeed needed to explore the pathogenesis and mechanism of RSTS.

鲁宾斯坦-泰比综合征（Rubinstein-Taybi Syndrome, RSTS）是一种罕见的先天性疾病，患者具有特征性面容、宽拇指与宽大足趾，且存在发育迟缓症状。RSTS由CREBBP及同源基因EP300的新发遗传变异所导致。本研究整合多重连接依赖探针扩增（multiplex ligation-dependent probe amplification, MLPA）与全外显子组测序（whole exome sequencing, WES）技术，建立了一套遗传诊断方案。本研究共纳入5名临床确诊为RSTS的患者进行遗传检测：采集患者及其家属的外周血以提取生殖系DNA。检测结果显示，1名患者（病例1）在16p13.3区域存在涵盖CREBBP基因的大片段杂合缺失；3名患者（病例2至4）携带不同的CREBBP基因变异（分别为c.2608C>T:p.Gln870Ter、c.4404_4405del:p.Thr1468fs、c.3649C>T:p.Gln1217Ter）；第5名RSTS患者（病例5）未检出致病性变异。本研究提出的分子诊断方案可在4/5的患者中检出致病性遗传改变，分子诊断率达80%。鉴于该疾病的罕见性，未来仍需开展更多研究以探索RSTS的发病机制与病理过程。