Costello综合征胎儿的遗传学分析并文献回顾

Genetic analysis and literature review of fetuses with Costello syndrome

摘要

目的 探讨Costello综合征胎儿的临床特征及致病基因的变异。方法 本研究选取2022年就诊于宁波市妇女儿童医院的两名孕妇作为研究对象,收集胎儿及家庭成员的临床资料和家族史,采用全外显子组测序(WES)分析患儿致病基因,确定可疑变异后对先证者及其父母进行Sanger测序验证,并在中国知网,万方数据库以及PubMed数据库中以“Costello综合征”,“Costello syndrome”,“prenatal diagnosis”,“HRAS”为关键词检索2000至2023年相关文献进行回顾分析。结果 胎儿1超声提示羊水过多,颈部水囊瘤,左心房偏小,肾盂分离,胃泡裂隙状,下颌略后缩.胎儿2超声提示羊水过多,心包积液,室壁增厚,左侧胸腔积液,肾盂分离,单脐动脉,下颌略后缩.WES结果为家系1胎儿携带HRAS基因的c.35G>T(p.G12V)杂合错义变异,家系2胎儿携带HRAS基因c.34G>T(p.G12C)杂合错义变异,两个家系父母亲均为野生型,Sanger测序验证两变异为新发变异.连同14篇文献报道的24例Costello综合征病例,多存在羊水过多(85%)、心血管异常(92%)、早产(83%)、特殊面容(81%)等临床症状,共检出7种HRAS基因变异,其中c.34G>A(p.G12S)突变占比最高(31%)。结论 Costello综合征胎儿的致病原因可能为HRAS基因的错义突变,Costello综合征可能存在基因型与表型的相关性.

Abstract

Objective To investigate the clinical characteristics and genetic variations associated with Costello syndrome in fetuses. Methods This study involved two pregnant women who visited Ningbo Women and Children's Hospital in 2022. Clinical data and family history of the fetuses and family members were collected. Whole-exome sequencing (WES) was used to analyze the pathogenic genes of the fetuses. After identifying suspicious variations, Sanger sequencing was conducted to verify these in the probands and their parents. A literature review from 2000 to 2023 was conducted on China National Knowledge Infrastructure (CNKI), Wanfang Database, and PubMed using keywords of “Costello syndrome” or “prenatal diagnosis” or “HRAS”. Results Fetus 1 ultrasound findings showed polyhydramnios, cystic hygroma in the neck, a smaller left atrium, renal pelvis separation, slit-like gastric bubble, and slight retrognathia. Fetus 2 ultrasound findings revealed polyhydramnios, pericardial effusion, thickened ventricular walls, left-sided pleural effusion, renal pelvis separation, single umbilical artery, and slight retrognathia. WES results identified that fetus 1 carried a de novo heterozygous missense mutation in the HRAS gene, c.35G>T (p.G12V), while fetus 2 carried a de novo heterozygous missense mutation in the HRAS gene, c.34G>T (p.G12C). Sanger sequencing confirmed these mutations as de novo in both cases, as the parents of both families were wild-type. Combined with a literature review of 14 articles reporting 24 cases of Costello syndrome, most cases exhibited clinical features such as polyhydramnios (85%), cardiovascular abnormalities (92%), preterm birth (83%), and distinctive facial features (81%). Seven HRAS gene mutations were identified, with the c.34G>A (p.G12S) mutation being the most common (31%). Conclusion The pathogenic cause of fetal Costello syndrome is missense mutations in the HRAS gene, and there may be a correlation between genotype and phenotype in Costello syndrome.

关键词

Costello综合征 / HRAS基因 / 全外显子组

Key words

Costello syndrome / HRAS gene / whole exome sequencing

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基金资助

宁波市品牌学科(PPXK2018G06)

宁波市科技计划项目(202002N3150)

宁波市医疗卫生高端团队项目(2022020405)

宁波巿社会公益项目(2022S035)