目的:探讨Rubinstein-Taybi综合征(RSTS)胎儿CREBBP基因变异的临床特征。
方法:选择2022年8月郑州大学第三附属医院确诊的RSTS胎儿作为研究对象。临床数据,收集胎儿的羊水样本及其父母的外周血样本进行全外显子组测序(WES)。通过Sanger测序验证候选变体。
结果:足部畸形,小脑疣,大脑发育不全,产前超声发现大脚趾和其他表型。WES显示胎儿具有杂合c.4684G>T(p。E1562*)CREBBP基因(NM_004380.3)外显子28中的变体,这是从头起源的。根据美国医学遗传学和基因组学学院(ACMG)的指南,预测该变体是致病性的(PVS1+PS2_中度+PM2_支持)。经过遗传咨询,这对夫妇选择终止妊娠,并拒绝对胎儿进行尸检。
结论:c.4684G>T(p。E1562*)CREBBP基因的变体可能位于该胎儿的RSTS之下。新发现的变体丰富了CREBBP基因的突变谱,并说明WES是RSTS产前诊断的有效工具。
OBJECTIVE: To explore the clinical characteristics and variant of CREBBP gene in a fetus with Rubinstein-Taybi syndrome (RSTS).
METHODS: A fetus with RSTS diagnosed at the Third Affiliated Hospital of Zhengzhou University in August 2022 was selected as the study subject. Clinical data, amniotic fluid sample of the fetus and peripheral blood samples of its parents were collected for whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing.
RESULTS: Foot malformation, cerebellar vermis agenesis, brain agenesis, polysyndactyly of the big toes and other phenotypes were found by prenatal ultrasound. WES revealed that the fetus has harbored a heterozygous c.4684G>T (p.E1562*) variant in exon 28 of the CREBBP gene (NM_004380.3), which was de novo in origin. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic (PVS1+PS2_Moderate+PM2_Supporting). After genetic counseling, the couple had opted to terminate the pregnancy and refused autopsy of the fetus.
CONCLUSIONS: The c.4684G>T (p.E1562*) variant of the CREBBP gene probably underlay the RSTS in this fetus. The newly discovered variant has enriched the mutational spectrum of the CREBBP gene and illustrated that WES is an efficient tool for the prenatal diagnosis of RSTS.