新生儿CHARGE综合征5例临床及基因变异分析

doi:10.12372/jcp.2023.22e0695

摘要/Abstract

摘要：

目的分析5例诊断为新生儿CHARGE综合征患儿的临床特征及基因变异特点，明确死亡患儿的遗传学病因。方法收集5例患儿的临床资料，应用高通量测序技术对5例疑诊CHARGE综合征患儿进行检测，利用Sanger测序技术对可疑位点和核心家系成员进行验证。结果 5例患儿均存在结构畸形合并喂养困难（均排除鼻后孔闭锁），其中2例出现歪嘴哭。3例患儿合并鼻腔狭窄或者上气道塌陷综合征，因治疗效果差，不能撤离呼吸机最终死亡；1例患儿因家属放弃治疗死于家中；1例目前随访中。家系1为CHD7基因c.478del（Y160Tfs*51）移码变异，家系2为CHD7基因c.5428C>T(P.R1810*)无义变异，家系3为CHD7基因c.6292C>T(P.R2098*)无义变异，家系4为CHD7基因c.4317delA（p.Q1440S fs*3）移码变异，家系5为CHD7基因c.469C>T(P.R157*)无义变异。5个家系的父母均未携带相应的变异，均为新发变异。其中家系4的CHD7基因c.4317delA为未报道的新变异。结论 CHD7基因变异可能为5例患儿的致病原因，其中4例患儿死亡的遗传学病因可能为CHD7基因变异导致的系统畸形。对于类似多发畸形患儿临床诊断的同时应积极完善基因检测明确遗传学诊断，以提高对该病的认识。

关键词: CHARGE综合征, CHD7基因, 新生儿

Abstract:

Objective To analyze the clinical features and gene variation characteristics of 5 children diagnosed with neonatal CHARGE syndrome, and to identify the genetic etiology of the deaths. Methods The clinical data of 5 children were collected. High-throughput sequencing technology was used to detect 5 children with suspected CHARGE syndrome, and Sanger sequencing technology was used to verify the suspicious loci and core family members. Results Clinical features of 5 cases: structural deformity combined with feeding difficulties (both excluded posterior nasal atresia), 2 children with crooked mouth crying, 3 children with nasal cavity stenosis or upper airway collapse syndrome who, due to poor treatment effect, could not be removed from the ventilator and eventually died, 1 patient's family members gave up treatment and died at home; 1 patient is currently being followed up. Family 1 had a frameshift variant of the CHD7 gene c.478del (Y160Tfs*51), family 2 had a nonsense variant of the CHD7 gene c.5428C>T (P.R1810*), and family 3 had a nonsense variant of the CHD7 gene c.6292C>T (P. R2098*), family 4 had a frameshift variant of the CHD7 gene c.4317delA (p.Q1440S fs*3), family 5 had a nonsense variant of the CHD7 gene c.469C>T (P.R157*). The parents of the 5 families did not carry the corresponding variats, and the varians were all de novo. The c.4317delA in family 4 was previously unreported. Conclusion The CHD7 gene mutation may be the pathogenic cause of 5 cases. The genetic cause of death in 4 cases may be system malformation caused by CHD7 gene mutation; for the clinical diagnosis of children with similar multiple malformations, the genetic testing should be actively improved to make the diagnosis clear, so as to improve the clinician's understanding of the disease.

Key words: CHARGE syndrome, CHD7 gene, newborn

王颍源, 方盼盼, 陈蒙蒙, 郭静, 刘大鹏, 康文清. 新生儿CHARGE综合征5例临床及基因变异分析[J]. 临床儿科杂志, 2023, 41(11): 846-851.

WANG Yingyuan, FANG Panpan, CHEN Mengmeng, GUO Jing, LIU Dapeng, KANG Wenqing. Analysis of clinical features and gene mutations in five neonates with CHARGE syndrome[J]. Journal of Clinical Pediatrics, 2023, 41(11): 846-851.

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参考文献 24

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项目	例1	例2	例3	例4	例5
性别	男	男	男	男	女
入院日龄/d	3	1	2	10	1
胎龄/周	36⁺⁵	39⁺⁵	39⁺⁴	40	40
主要临床表现	生后呼吸困难，反应差，不明原因呼吸心跳骤停	反应差，呼吸困难	呼吸困难，喂养困难，反应差2 d	吃奶差10 d，抽搐4 d	产时窒息，反应差，呼吸困难，吐沫
眼部病变	双侧先天性虹膜及脉络膜缺损	无	脉络膜缺损	无	双侧脉络膜缺失
鼻咽腔发育	喉软骨软化，双侧鼻腔狭窄，上气道塌陷综合征	上气道塌陷综合征，鼻腔狭窄	鼻腔狭窄	鼻腔狭窄	上气道塌陷综合征，鼻腔狭窄
颅神经功能障碍	SNHL，吞咽协调障碍，面瘫	SNHL，吞咽协调障碍	SNHL，吞咽协调障碍	SNHL，吞咽协调障碍	SNHL，吞咽协调障碍，面瘫
耳部畸形	褶皱异常，无耳垂	褶皱异常，无耳垂	耳廓外形及耳屏均存在畸形	外耳廓褶皱异常	耳廓小，无耳垂
内分泌系统	阴茎短小，隐睾	阴茎短小，隐睾	隐睾	阴茎短小，隐睾	无
心血管畸形	PFO，PDA	ASD，VSD，PH，PDA	三尖瓣下移畸形，ASD，VSD，PH，PDA	ASD，PDA	ASD，PDA
是否接受心脏手术	否	术前围手术期死亡	否	是	否
呼吸机辅助通气	反复多次撤机均失败	反复多次撤机均失败	无	呼吸机辅助通气，心脏病术后撤机，并逐渐停氧顺利	反复多次撤机均失败
血尿串联质谱	阴性	阴性	阴性	阴性	阴性

病例	核苷酸改变	氨基酸改变	ExAC	ESP6500	千人基因组	变异来源	已报道
1	c.478del	Y160Tfs*51	NA	NA	NA	新发变异	已知^[5]
2	c.5428C>T	R1810*	NA	NA	NA	新发变异	已知^[6]
3	c.6292C>T	R2098*	NA	NA	NA	新发变异	已知^[7]
4	c.4317delA	p.Q1440Sfs3	NA	NA	NA	新发变异	本研究
5	c.469C>T	R157*	NA	NA	NA	新发变异	已知^[8]

病例	基因	ACMG证据	ACMG评级	评级依据
1	CHD7	导致氨基酸移码，LOF变异导致基因功能可能丧失（PVS1）；经双亲验证的新发变异（PS2）；参考ExAC和1000g正常人群数据库，该变异未收录（PM2）	致病	PVS1+PS2+PM2
2	CHD7	LOF变异导致基因功能可能丧失（PVS1）；经双亲验证的新发变异（PS2）；ExAC和1000g正常人群数据库，该变异未收录（PM2）	致病	PVS1+PS2+PM2
3	CHD7	LOF变异导致基因功能可能丧失（PVS1）；经双亲验证的新发变异（PS2）；ExAC和1000g正常人群数据库，该变异未收录（PM2）	致病	PVS1+PS2+PM2
4	CHD7	导致氨基酸移码，LOF变异导致基因功能可能丧失（PVS1）；经双亲验证的新发变异（PS2）；参考ExAC和1000g正常人群数据库，该变异未收录（PM2）	致病	PVS1+PS2+PM2
5	CHD7	LOF变异导致基因功能可能丧失（PVS1）；经双亲验证的新发变异（PS2）；ExAC和1000g正常人群数据库，该变异未收录（PM2）	致病	PVS1+PS2+PM2