云南地区永久性先天性甲状腺功能减退症患儿基因突变分析

doi:10.3724/zdxbyxb-2022-0199

浙江大学学报（医学版）

2022, Vol. 51

Issue (3): 306-313 DOI: 10.3724/zdxbyxb-2022-0199

专题报道

云南地区永久性先天性甲状腺功能减退症患儿基因突变分析

龚彦菱^1,²,章印红³,刘凡⁴,朱宝生³,周笑颜³,镡颖³,李苏云³,李利^1,^2,*(

)

1.昆明理工大学医学院，云南昆明 650500
2.云南省第一人民医院昆明理工大学附属医院儿科，云南昆明 650032
3.云南省第一人民医院昆明理工大学附属医院医学遗传科云南省出生缺陷与遗传病研究重点实验室云南省出生缺陷与罕见病临床医学研究中心，云南昆明 650032
4.楚雄彝族自治州人民医院儿童医学中心，云南楚雄 675000

Gene mutations in children with permanent congenital hypothyroidism in Yunnan, China

GONG Yanling^1,²,ZHANG Yinhong³,LIU Fan⁴,ZHU Baosheng³,ZHOU Xiaoyan³,CHAN Ying³,LI Suyun³,LI Li^1,^2,*(

)

1. School of Medicine, Kunming University of Science and Technology, Kunming 650500, China;
2. Department of Pediatrics, the First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, China;
3. Department of Medical Genetics, the First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Yunnan Provincial Key Laboratory for Birth Defects and Genetic Diseases, Yunnan Provincial Clinical Research Center for Birth Defects and Rare Diseases, Kunming 650032, China;
4. Children’s Medical Center, Chuxiong Yi Autonomous Prefecture People’s Hospital, Chuxiong 675000, Yunnan Province, China

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摘要：

目的：分析云南地区永久性先天性甲状腺功能减退症（CH）患儿的基因突变及其临床表型特点。方法：回顾性分析2016年1月至2019年1月经云南省第一人民医院诊治的40例CH患儿的临床资料，所有患儿随访至3岁，分别在患儿1、2和3岁时行格塞尔发育量表评分，评估患儿发育状况和预后。采用高通量测序检测27个已知的CH相关基因，分析基因型和临床表型之间的关系。结果：40例患儿中23例检出相关基因突变，突变检出率为57.5%；共检出8个基因的32种突变类型，前三位突变基因为DUOX2、TPO和TSHR，突变频率分别为65.9%（29/44）、11.4%（5/44）和9.1%（4/44）；17例检出DUOX2基因突变患儿存在17种突变类型，其中p.K530*突变频次最高，占比20.7%（6/29）；DUOX2杂合突变与复合杂合突变患儿的体格发育和智力发育评估差异无统计学意义（P>0.05），患儿随访至3岁均不能停药，表现为永久性CH。携带其他基因突变患儿的体格和智力发育评估也在正常范围。结论：云南地区永久性CH患儿DUOX2、TPO和TSHR基因突变检出率较高，基因突变类型与CH患儿预后无明显相关性。

关键词： 先天性甲状腺功能减退症; 基因突变; 新生儿筛查; 甲状腺激素; 高通量测序

Abstract:

Objective: To investigate molecular and clinical characteristics of children with permanent congenital hypothyroidism (CH) in Yunnan, China. Methods: The clinical data of 40 children with CH diagnosed and treated in the First People’s Hospital of Yunnan Province during January 2016 and January 2019 were retrospectively analyzed. All children were followed up to 3?years old, and Gesell intelligent score was evaluated at age of 1, 2 and 3?years, respectively. Developmental status and prognosis were evaluated. Next-generation sequencing (NGS) was used to screen all exons and exon-intron boundary sequences of the 27 known CH associated genes, and the relationship between genotypes and clinical phenotypes was analyzed. Results: Among the 40 children, the thyroid related pathogenic gene mutations were detected in 23 cases with a rate of 57.5%, and a total of 32 mutations of 8 genes were detected. Mutations in DUOX2, TPO and TSHR genes were the most common ones with mutation frequencies of 65.9%(29/44), 11.4%(5/44) and 9.1%(4/44), respectively. DUOX2 gene mutations were detected in 17 children with CH, and a total of 17 mutation types were detected. p.K530* was the most common mutation in DUOX2 gene, accounting for 20.7%(6/29). There was no significant difference in physical development and intelligence assessment between children with DUOX2 heterozygous mutation and compound heterozygous mutations. None of patients could terminate medication at 3?years of the follow-up and all of them were provisionally assessed as permanent CH. The physical and mental development assessment of children with other gene mutations were also in the normal range. Conclusion: The detection rate of DUOX2, TPO and TSHR pathogenic mutations are high among children with permanent CH in Yunnan area, and no correlation is observed between gene mutation types and prognosis in children with CH.

Key words: Congenital hypothyroidism Gene mutation Neonatal screening Thyroid hormone High-throughput sequencing

收稿日期: 2022-04-24 出版日期: 2022-09-21

CLC:

R722.11

基金资助: 云南省万人计划“名医”专项（YNWR-MY-2018-016）；云南省科技厅–昆明医科大学应用基础研究联合专项（202101AY070001-262）；云南省出生缺陷;遗传病研究重点实验室开放课题（2020ZDKFKT001）；云南省出生缺陷与罕见病临床医学研究中心项目（2019ZF015）

通讯作者: 李利 E-mail: erklili@sina.com

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引用本文:

龚彦菱,章印红,刘凡,朱宝生,周笑颜,镡颖,李苏云,李利. 云南地区永久性先天性甲状腺功能减退症患儿基因突变分析[J]. 浙江大学学报（医学版）, 2022, 51(3): 306-313.

GONG Yanling,ZHANG Yinhong,LIU Fan,ZHU Baosheng,ZHOU Xiaoyan,CHAN Ying,LI Suyun,LI Li. Gene mutations in children with permanent congenital hypothyroidism in Yunnan, China. J Zhejiang Univ (Med Sci), 2022, 51(3): 306-313.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0199 或 https://www.zjujournals.com/med/CN/Y2022/V51/I3/306

突变基因（转录本）	区域	突变位点	氨基酸变化	突变类型	致病等级	突变频数	占比（%）
DUOX2（NM_014080.4）	外显子14	c.1588A>T	p.K530*	无义	致病	6	13.6
	外显子17	c.2048G>T	p.R683L	错义	可能致病	3	6.8
	外显子20	c.2654G>T	p.R885L	错义	可能致病	3	6.8
	外显子28	c.3693+1G>T	splicing	剪切	致病	3	6.8
	外显子25	c.3329G>A	p.R1110Q	错义	可能致病	2	4.5
	外显子6	c.605_621delAGCTGGCGTCGGGGCCC	p.Gln202Argfs*93	缺失	致病	1	2.3
	外显子6	c.647_656delAGAACCCCCTinsTTTCCCCCGAGACTC	p.delGluAsnProLeu216_219insLeuSerProGluThrArgfs*81	缺失	致病	1	2.3
	外显子13	c.1462G>A	p.G488R	错义	可能致病	1	2.3
	外显子13	c.1546C>T	p.R516C	错义	临床意义未明	1	2.3
	外显子15	c.1708C>T	p.Q570*	无义	可能致病	1	2.3
	外显子17	c.2054T>C	p.V685A	错义	临床意义未明	1	2.3
	外显子20	c.2635G>A	p.E879K	错义	致病	1	2.3
	外显子22	c.2921G>A	p.R974H	错义	临床意义未明	1	2.3
	外显子25	c.3391G>T	p.A1131S	错义	临床意义未明	1	2.3
	外显子30	c.3974A>G	p.H1325R	错义	临床意义未明	1	2.3
	外显子32	c.4348T>C	p.Y1450H	错义	临床意义未明	1	2.3
	外显子34	c.4537G>C	p.G1513R	错义	临床意义未明	1	2.3
TPO（NM_ 000547.5）	外显子9	c.1450G>A	p.V484M	错义	可能致病	1	2.3
	外显子9	c.1471C> T	p.R491C	错义	可能致病	1	2.3
	外显子10	c.1682C>T	p.T561M	错义	可能致病	1	2.3
	外显子11	c.1949G>A	p.G650E	错义	临床意义未明	1	2.3
	外显子13	c.2268dupT	p.E757*	无义	致病	1	2.3
TSHR（NM_000369.2）	外显子10	c.1295A>G	p.N432S	错义	可能致病	1	2.3
	外显子10	c.1454C>A	p.A485D	错义	可能致病	1	2.3
	外显子10	c.1538C>T	p.T513M	错义	可能致病	1	2.3
	外显子10	c.1638G>A	p.W546*	无义	可能致病	1	2.3
TBL1X（NM_005647.3）	外显子5	c.139C>T	p.R47*	无义	可能致病	1	2.3
TBL1X（NM_005647.3）	外显子7	c.611C>A	p.S204*	无义	可能致病	1	2.3
PAX8（NM_003466.3）	外显子3	c.164A>G	p.H55R	错义	临床意义未明	1	2.3
IYD（NM_203395.2）	外显子4	c.599G>C	p.G200A	错义	临床意义未明	1	2.3
IGSF1（NM_001170961.1）	外显子14	c.2471C>T	p.S824F	错义	临床意义不明	1	2.3
DUOXA2（NM_207581.3）	外显子5	c.738C>G	p.Y246*	无义	可能致病	1	2.3

表 1 23例先天性甲状腺功能减退症患儿8个突变基因的32种突变类型一览

表 2 17例基因突变先天性甲状腺功能减退症患儿基因型及表型

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