Clinical features and genetic analysis of Rubinstein-Taybi syndrome：three cases report and literature review

doi:10.3877/cma.j.issn.1673-5250.2024.04.013

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.

Key words: Rubinstein-Taybi syndrome, CREBBP gene, Whole-exome-sequencing, Polymerase chain reaction, Gene mutation, Protein three-dimensional structure prediction, Child

图1 Rubinstein-Taybi综合征先证者1（男性，6岁9个月龄）面容及手部照片图（图1A：眼裂下斜、内眦赘皮、宽眼距、鼻根凹陷、鼻梁宽阔、薄上唇；图1B：耳后瘘管；图1C：双手通贯掌、铲状拇指；图1D：双手小指弯曲）

图2 Rubinstein-Taybi综合征先证者2（男性，2 岁1 个月龄）面容及手部照片图（图2A：眼裂下斜、内眦赘皮、宽眼距、鼻梁宽阔；图2B：宽短手，铲状拇指）

图3 Rubin stein-Taybi综合征先证者1（男性，6岁9个月龄）CREBBP 基因第5、15号外显子单倍重复荧光柱状示意图注：P为先证者1，F为先证者1父亲，M 为先证者1母亲，C1/C2/C3分别为3个基因芯片检测拷贝数正常成年女性对照

图4 Rubin stein-Taybi综合征先证者2（男性，2岁1个月龄）及其父、母亲CREBBP 基因c.5384G＞T 变异Sanger测序图［图4A：先证者2携带CREBBP 突变基因c.5384G＞T（p.Cys1795Phe）杂合变异（箭头所示）；图4B、4C：先证者2父亲及母亲均为CREBBP 基因野生型（箭头所示）］

图5 Rubin stein-Taybi综合征先证者3（女性，9个月龄）及其父、母亲CREBBP基因Sanger测序结果［图5A：先证者3携带CREBBP 突变基因c.1409T＞A（p.Leu470*）杂合变异（箭头所示）；图5B、5C：先证者3父亲及母亲均为CREBBP 基因野生型（箭头所示）］

图6 CREBBP蛋白结构域示意图

图7 CBEBBP蛋白氨基酸序列保守性预测分析（红框所示为p.Cys1795）注：Homo sapiens 为人类，Pan troglodytes 为大猩猩，Macaca mulatta为猕猴，Canis lupus familiaris为犬，Bos taurus为牛，Mus musculus为家鼠，Rattus norvegicus为褐家鼠

图8 野生型与突变型CREBBP 蛋白三维结构预测图［图8A：野生型CREBBP 蛋白的三维结构预测图；图8B：野生型Cys1795局部结构；图8C：突变型Phe1795 的苯环与周围残基的空间能垒明显增大（蓝色虚线框中所示）；图8D：突变型Phe1795］注：玫红色表示野生型及突变体氨基酸，黄、绿、橙、紫色表示与其形成氢键连接的局部氨基酸；红线表示氢键，数字表示氢键键能

表1 先证者2、3基因检测结果

先证者	基因	染色体位置^a	NM号	外显子	HGVS	纯合/杂合	致病性分析（评级证据）	变异
先证者2	CREBBP	Chr16：3729663	NM_004380.3	exon31	c.5384G＞T（p.Cys1795Phe）	杂合	疑似致病性变异（PM6+PM2_Supporting+PP2+PP3）	新发变异
先证者3	CREBBP	Chr16：3782848	NM_004380.3	exon6	c.1409T＞A（p.Leu470*）	杂合	致病性变异（PVS1+PS2+PM2_Supporting）	新发变异

表1 先证者2、3基因检测结果

先证者	基因	染色体位置^a	NM号	外显子	HGVS	纯合/杂合	致病性分析（评级证据）	变异
先证者2	CREBBP	Chr16：3729663	NM_004380.3	exon31	c.5384G＞T（p.Cys1795Phe）	杂合	疑似致病性变异（PM6+PM2_Supporting+PP2+PP3）	新发变异
先证者3	CREBBP	Chr16：3782848	NM_004380.3	exon6	c.1409T＞A（p.Leu470*）	杂合	致病性变异（PVS1+PS2+PM2_Supporting）	新发变异

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