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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 Yanling1,2,ZHANG Yinhong3,LIU Fan4,ZHU Baosheng3,ZHOU Xiaoyan3,CHAN Ying3,LI Suyun3,LI Li1,2,*()
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DUOX2TPOTSHR,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DUOX2TPOTSHR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        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

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

例序

性别

确诊时年龄(d)

TSH (mIU/L)

FT4 (pmol/L)

甲状腺超声检查

DUOX2基因氨基酸变异(遗传来源)

合并其他基因突变

3岁时左甲状腺素剂量(μg/d)

初筛

复查

1

29

333.0

118.0

4.8

正常

p.H1325R(母)

PAX8

80.0

2

16

103.0

98.0

5.4

缺如

p.V685A(母)

TPO

75.0

3

15

20.0

17.0

5.0

正常

p.R885L(母)

17.5

4

27

70.9

100.0

2.9

增大

p.R1110Q(—)

60.0

5

18

25.0

19.0

9.4

正常

p.K530*(父)

40.0

6

23

12.3

46.9

9.9

增大

p.K530*(父)/p.R1110Q(母)

37.5

7

15

10.7

15.6

10.2

增大

p.K530*(父)/p.R885L(母)

37.5

8

25

92.8

150.0

0.3

偏小

p.R885L(母)/p.Q570*(父)

IYD

62.5

9

18

131.0

124.7

7.1

正常

p.K530*(父)/splicing(母)

75.0

10

19

237.0

14.2

9.2

增大

p.A1131S(—)/p.R974H(母)

25.0

11

26

17.9

71.9

6.1

增大

p.K530*(母)/splicing(—)

TPO

37.5

12

30

32.4

111.9

5.1

正常

p.K530*(父)/p.Y1450H(母)

37.5

13

15

23.0

16.5

5.0

增大

p.E879K(母)/p.R516C(父)

30.0

14

22

28.0

9.8

5.1

正常

p.R683L(母)/p.G488R(父)

20.0

15

17

110.0

100.0

5.6

增大

p.R683L(父)/splicing(母)

25.0

16

24

25.4

38.5

8.1

增大

p.R683L(父)/p.G1513R(—)

25.0

17

20

85.0

67.0

7.9

正常

p.Gln202Argfs*93(父)/p.delGluAsnProLeu216_219insLeuSerProGluThrArgfs*81(母)

62.5

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

突变类型

n

身高

(cm)

体重

(kg)

头围

(cm)

格塞尔发育量表评分

左甲状腺素治疗剂量(μg/d)

大运动

精细运动

适应性行为

语言

个人–社会行为

杂合突变

?

1岁

5

74.9±1.7

9.8±0.7

45.7±1.1

90.4±6.6

95.8±3.7

94.4±3.6

95.2±4.2

98.8±0.8

26.2±10.7

2岁

5

87.7±3.1

12.7±1.6

48.3±0.8

93.2±6.6

89.8±3.3

91.2±3.8

87.0±6.3

91.6±5.9

32.0±15.4

3岁

5

95.9±1.8

13.9±1.6

49.1±0.7

91.6±4.1

95.4±5.2

94.4±2.4

95.4±5.3

97.0±4.5

36.0±24.6

复合杂合突变

?

1岁

12

75.0±1.1

9.6±0.4

46.3±1.1

91.3±6.8

92.9±6.8

90.2±7.5

87.3±7.8

94.1±6.0

26.0±7.6

2岁

12

87.4±2.7

12.3±1.0

47.8±0.8

92.9±6.2

93.7±8.2

94.9±8.0

87.7±9.6

97.0±6.1

30.2±9.0

3岁

12

95.6±3.0

14.5±1.1

48.6±0.8

94.3±7.6

96.6±5.6

95.3±6.4

88.1±8.4

97.5±7.2

29.0±6.6

  
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