CHARGE综合征7例患儿的临床表型及分子遗传学分析  

Clinical phenotype and molecular genetic analysis of seven children with CHARGE syndrome

作　　者：葛丽丽[1] 孔京慧 陈重芬 夏志毅 梅世月 张耀东 Ge Lili;Kong Jinghui;Chen Chongfen;Xia Zhiyi;Mei Shiyue;Zhang Yaodong(Henan Key Laboratory for Children′s Genetics and Metabolic Diseases,Children′s Hospital Affiliated to Zhengzhou University,Henan Children′s Hospital,Zhengzhou Children′s Hospital,Zhengzhou,Henan 450018,China)

机构地区：[1]郑州大学附属儿童医院,河南省儿童医院郑州儿童医院,河南省儿童遗传代谢性疾病重点实验室,郑州450018

出　　处：《中华医学遗传学杂志》2024年第9期1053-1058,共6页Chinese Journal of Medical Genetics

基　　金：郑州市第一层次名医培养对象项目(郑人社办[2022]88号)。

摘　　要：目的探讨7例CHARGE综合征(CS)患儿的临床表型及遗传学病因。方法回顾性分析2020年3月至2022年12月就诊于郑州大学附属儿童医院的7例CS患儿的临床资料,采集患儿及其父母的外周血样,提取基因组DNA,对其进行全外显子组测序。对候选变异进行Sanger测序家系验证及致病性分析。本研究通过郑州大学附属儿童医院医学伦理委员会的审查(伦理号:2024-K-023)。结果7例患儿首诊年龄为出生后1 d~12岁不等,均存在生长发育迟缓,5例患儿首诊原因为出生后呼吸、吞咽及喂养困难,1例因外生殖器异常伴听力障碍就诊,1例因青春期第二性征未发育就诊。7例患儿均检测出CHD7基因变异:c.6292C>T(p.R2098*)、c.2754G>A(p.W918*)、c.469C>T(p.R157*)、c.3308T>A(p.V1103D)、c.7111delC(p.Q2371Kfs)、c.6023delA(p.D2008Vfs)、c.3565C>T(p.R1189C),包括3个无义变异、2个移码变异、2个错义变异。经Sanger测序验证,上述变异均为新发。经生物信息学预测及美国医学遗传学与基因组学学会(ACMG)相关指南评级,c.3308T>A(p.V1103D)与c.3565C>T(p.R1189C)被评定为可能致病性变异(PS2+PM2_Supporting+PP3),其余均被评定为致病性变异(PVS1+PS2+PM2_Supporting)。结论CS的临床与遗传异质性较强,早期进行基因检测有利于准确诊断,避免漏诊与误诊。上述新变异位点的检出拓展了CS的表型谱及CHD7基因的变异谱。ObjectiveTo explore the clinical phenotype and genetic etiology for seven children with CHARGE syndrome(CS).MethodsClinical data of 7 children with CS diagnosed between March 2020 and December 2022 at the Children′s Hospital Affiliated to Zhengzhou University were analyzed.Genomic DNA was extracted from peripheral blood samples from the children and their parents,and subjected to whole exome sequencing.Candidate variants were verified by Sanger sequencing and pathogenicity analysis.This study was approved by the Medical Ethics Committee of the Children′s Hospital Affiliatedto Zhengzhou University(Ethics No.2024-K-023).ResultsThe ages of the children had ranged from 1 day after birth to 12 years old,and all of them had shown growth retardation.The reasons for their admission had included postnatal breathing,swallowing and feeding difficulties in five cases.One child was found to have abnormal external genitalia in conjunct with hearing impairment,whilst another child had shown no secondary sexual characteristics during puberty.All of the children were found to harbor CHD7 gene variants,which included 3 nonsense variants,2 frameshifting variants and 2 missense variants,i.e.,c.6292C>T(p.R2098*),c.2754G>A(p.W918*),c.469C>T(p.R157*),c.3308T>A(p.V1103D),c.7111delC(p.Q2371Kfs),c.6023delA(p.D2008Vfs)and c.3565C>T(p.R1189C).All of the variants were de novo in origin.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the c.3308T>A(p.V1103D)and c.3565C>T(p.R1189C)variants were rated as likely pathogenic(PS2+PM2_Supporting+PP3),whilst the remainders were rated as pathogenic(PVS1+PS2+PM2_Supporting).ConclusionThere is strong clinical and genetic heterogeneity in CS.Early genetic testing may facilitate accurate diagnosis.The detection of novel variants has expanded the phenotypic spectrum of CS and the mutational spectrum of the CHD7 gene.

关 键 词：CHARGE综合征 CHD7基因 先天性多发畸形 

分 类 号：R725.9[医药卫生—儿科]