利用全外显子测序在肥胖人群中筛查致病突变

doi:10.3969/j.issn.1674-8115.2023.07.010

上海交通大学学报（医学版） ›› 2023, Vol. 43 ›› Issue (7): 882-889.doi: 10.3969/j.issn.1674-8115.2023.07.010

• 论著 · 临床研究 • 上一篇

利用全外显子测序在肥胖人群中筛查致病突变

王景慧¹^,²(), 张红³, 张蓉³, 彭丹凤³, 余海蓉³, 陈香慧³, 宣晔³, 胡承³(), 顾云娟¹^,⁴()

^1.南通大学附属医院内分泌与代谢科，南通 226001
^2.南通大学医学院，南通 226019
^3.上海交通大学医学院附属第六人民医院内分泌代谢科，上海市糖尿病研究所，上海市糖尿病重点实验室，上海市糖尿病临床医学中心，上海 200233
^4.南通大学附属医院健康医学科，南通 226001

收稿日期:2023-02-17 接受日期:2023-06-30 出版日期:2023-07-28 发布日期:2023-07-28
通讯作者: 胡承,顾云娟 E-mail:jh.wang12@foxmail.com;alfaedhc@sjtu.edu.cn;desette@ntu.edu.cn
作者简介:王景慧（1996—），女，硕士；电子信箱：jh.wang12@foxmail.com。
基金资助:
上海市重点临床专科建设项目;上海市内分泌代谢疾病研究中心(2022ZZ01002);上海交通大学医工交叉研究基金(YG2021ZD20);上海市第六人民医院院级科研基金(ynhg202204)

Screening for pathogenic variants in obese cohort using whole-exome sequencing

WANG Jinghui¹^,²(), ZHANG Hong³, ZHANG Rong³, PENG Danfeng³, YU Hairong³, CHEN Xianghui³, XUAN Ye³, HU Cheng³(), GU Yunjuan¹^,⁴()

^1.Department of Endocrinology and Metabolism, Affiliated Hospital of Nantong University, Nantong 226001, China
^2.Medical School, Nantong University, Nantong 266019, China
^3.Department of Endocrine and Metabolic Diseases, Shanghai Sixth People′s Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Diabetes Institute; Shanghai Key Laboratory of Diabetes Mellitus; Shanghai Clinical Centre for Diabetes, Shanghai 200233, China
^4.Department of Health Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China

Received:2023-02-17 Accepted:2023-06-30 Online:2023-07-28 Published:2023-07-28
Contact: HU Cheng,GU Yunjuan E-mail:jh.wang12@foxmail.com;alfaedhc@sjtu.edu.cn;desette@ntu.edu.cn
Supported by:
Shanghai Municipal Key Clinical Specialty Construction Project;Shanghai Research Center for Endocrine and Metabolic Diseases(2022ZZ01002);Medical-Engineering Cross Foundation of Shanghai Jiao Tong University(YG2021ZD20);Shanghai Sixth People′s Hospital Grant(ynhg202204)

摘要/Abstract

摘要：

目的·利用全外显子测序技术（whole-exome sequencing，WES）筛查瘦素-促黑素细胞激素（leptin-melanocyte stimulating hormone，LEP-MSH）通路中的关键基因在肥胖人群中的突变情况。方法·招募2011年1月—2019年7月在上海交通大学医学院附属第六人民医院接受袖状胃切除术的119名肥胖患者：年龄17~65岁，体质量指数（body mass index，BMI）≥34 kg/m²。采集研究对象的外周血，提取全基因组DNA并进行全外显子测序，应用生物信息学方法筛选LEP-MSH通路上16个基因（ADCY3、AGRP、BDNF、KSR2、LEP、LEPR、MC3R、MC4R、MCHR1、MRAP2、NTRK2、PCSK1、PHIP、POMC、SH2B1和SIM1）的突变。选取1000 Genomes（1000G）、Exome Aggregation Consortium（ExAC）和Genome Aggregation Database（gnomAD）数据库中总人群最小等位基因频率小于0.02且东亚人群频率小于0.01的罕见变异位点用于后续分析。使用6种突变有害性预测软件来评估变异的损害程度。最后，基于每位患者的临床信息，并根据美国医学遗传学和基因组学学院（America College of Medical Genetics and Genomics，ACMG）指南对所有变异进行致病性判断，仅保留“致病的”“可能致病的”“意义不明的”突变。结果·119名患者中有24名患者检测到了LEP-MSH通路中16个关键基因的26个22种突变，均为杂合突变；其中SH2B1基因突变7个（占总突变数的26.92%），MCHR1基因突变4个（占15.38%），PHIP基因突变3个（占11.53%），ADCY3、LEPR基因突变各2个（各占7.69%），LEP、NTRK2、AGRP、KSR2、MC3R、MC4R、BDNF、PCSK1基因突变各1个（各占3.85%）。3名患者携带SH2B1基因上的相同变异位点，LEPR基因和MCHR1基因上分别有2名患者携带相同变异位点。共有12种变异在3个数据库的东亚人群中都没有被收录，为东亚人群新发变异，分别位于SH2B1（p.V209I、p.R67C、p.L149F）、KSR2（p.P155T）、LEP（p.D106N）、LEPR（p.W132R）、PHIP（p.K1461R）、BDNF（p.N84S）、PCSK1（p.R282W）、NTRK2（p.T732M）、MC3R（p.S71P）和MC4R（p.W174X）。结论·共检测到LEP-MSH通路上22种肥胖可能相关的罕见变异，其中12种为东亚人群新发变异。

关键词: 肥胖, 全外显子测序, 瘦素-促黑素细胞激素通路, 基因变异

Abstract:

Objective ·To screen mutations of key genes in the leptin-melanocyte stimulating hormone (LEP-MSH) pathway by whole-exome sequencing (WES) in the obese cohort. Methods ·A total of 119 obese patients aged 17－65 years old with body mass index (BMI)≥34 kg/m², who underwent laparoscopic sleeve gastrectomy from January 2011 to July 2019 at Shanghai Sixth People′s Hospital, Shanghai Jiao Tong University School of Medicine were collected. The peripheral blood samples of the research subjects were collected, and whole genome DNA was extracted to perform WES. Bioinformatic methods were applied to detect the mutations in 16 genes in the LEP-MSH pathway (ADCY3, AGRP, BDNF, KSR2, LEP, LEPR, MC3R, MC4R, MCHR1, MRAP2, NTRK2, PCSK1, PHIP, POMC, SH2B1,and SIM1). Rare variants with the minor allele frequency in the total population less than 0.02 and in the East Asian population less than 0.01 in the 1000 Genome (1000G), Exome Aggregation Consortium (ExAC) and Genome Aggregation Database (gnomAD) were selected for subsequent analysis. Six pieces of prediction software were used to evaluate the deleteriousness of the mutations. Finally, based on the clinical information of each patient, the pathogenicity of all variants was determined according to the guidelines of America College of Medical Genetics and Genomics (ACMG), and only the "pathogenic", "likely pathogenic", and "uncertain significance" variants were retained. Results ·A total of 26 variants, 22 kinds of variants were detected in 24 patients from 119 subjects, all of which were heterozygous mutations. The detected variants included 7 in SH2B1 gene (accounting for 26.92% of the total variants), 4 in MCHR1 gene (accounting for 15.38%), 3 in PHIP gene (accounting for 11.53%), 2 in ADCY3 and LEPR genes (accounting for 7.69%, respectively), and 1 in LEP, NTRK2, AGRP, KSR2, MC3R, MC4R, BDNF, and PCSK1 genes, respectively (accounting for 3.85%, respectively). There were 3 patients having the same mutation site in SH2B1 gene, and 2 patients having the same mutation sites in LEPR gene and MCHR1 gene, respectively. In addition, among these mutations, there were 12 ones not included in the East Asian population in 3 public databases, which were novel mutations in the East Asian population, located in SH2B1 (p.V209I, p.R67C, and p.L149F), KSR2 (p.P155T), LEP (p.D106N), LEPR (p.W132R), PHIP (p.K1461R), BDNF (p.N84S), PCSK1 (p.R282W), NTRK2 (p.T732M), MC3R (p.S71P), and MC4R (p.W174X). Conclusion ·A total of 22 kinds of rare variations possibly associated with obesity in the LEP-MSH pathway are detected, 12 of which are novel in the East Asian population.

Key words: obesity, whole-exome sequencing (WES), leptin-melanocyte stimulating hormone pathway, gene mutation

中图分类号:

R589.2

王景慧, 张红, 张蓉, 彭丹凤, 余海蓉, 陈香慧, 宣晔, 胡承, 顾云娟. 利用全外显子测序在肥胖人群中筛查致病突变[J]. 上海交通大学学报（医学版）, 2023, 43(7): 882-889.

WANG Jinghui, ZHANG Hong, ZHANG Rong, PENG Danfeng, YU Hairong, CHEN Xianghui, XUAN Ye, HU Cheng, GU Yunjuan. Screening for pathogenic variants in obese cohort using whole-exome sequencing[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(7): 882-889.

图/表 3

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Sample ID	ACMG	Gene	Chromosome	Position	dbSNP	MAF in EAS	SNV class	DNA/AA change	Degree of damage	GERP score
1	Pathogenic	NTRK2	chr9	87635191	rs367769334	Novel	Nonsynonymous	c.C2195T/p.T732M	DVS	6.16
2	Likely pathogenic	MCHR1	chr22	41077612	rs182594063	0.001 0	Nonsynonymous	c.C949T/p.R317W	DS	4.19
3	VUS	MCHR1	chr22	41077832	rs190547628	0.007 4	Nonsynonymous	c.G1169A/p.R390H	D	5.40
4	VUS	SH2B1	chr16	28878040	‒	Novel	Nonsynonymous	c.G625A/p.V209I	B	-1.84
5	Pathogenic	AGRP	chr16	67516606	rs199927717	0.001 0	Nonsynonymous	c.G332A/p.R111H	DS	6.17
6	VUS	SH2B1	chr16	28883185	rs200463987	0.005 1	Nonsynonymous	c.T386C/p.M129T	DW	5.14
7	VUS	KSR2	chr12	118199252	‒	Novel	Nonsynonymous	c.C463A/p.P155T	B	2.72
8	Likely pathogenic	LEP	chr7	127894628	‒	Novel	Nonsynonymous	c.G316A/p.D106N	D	3.86
9	Pathogenic	LEPR	chr1	66038032	‒	Novel	Nonsynonymous	c.T394C/p.W132R	DS	4.17
10	Pathogenic	LEPR	chr1	66038032	‒	Novel	Nonsynonymous	c.T394C/p.W132R	DS	4.17
11	VUS	ADCY3	chr2	25050847	rs78678013	0.000 6	Nonsynonymous	c.G2356A/p.A786T	DW	4.50
12	Pathogenic	PHIP	chr6	79655966	‒	Novel	Nonsynonymous	c.A4382G/p.K1461R	D	6.17
13	Pathogenic	MC3R	chr20	54824110	‒	Novel	Nonsynonymous	c.T211C/p.S71P	D	4.00
14	Pathogenic	SH2B1	chr16	28877614	rs781063312	Novel	Nonsynonymous	c.C199T/p.R67C	DS	4.71
	Pathogenic	SH2B1	chr16	28878223	rs561413284	0.001 9	Nonsynonymous	c.C808T/p.R270W	DS	3.96
15	Likely pathogenic	MCHR1	chr22	41077283	rs188147970	0.003 0	Nonsynonymous	c.C620T/p.A207V	D	5.02
16	VUS	BDNF	chr11	27679861	‒	Novel	Nonsynonymous	c.A251G/p.N84S	B	-9.56
17	VUS	SH2B1	chr16	28883185	rs200463987	0.005 1	Nonsynonymous	c.T386C/p.M129T	DW	5.14
18	Pathogenic	PCSK1	chr5	95748060	rs773564429	Novel	Nonsynonymous	c.C844T/p.R282W	DVS	0.38
19	Pathogenic	SH2B1	chr16	28877860	‒	Novel	Nonsynonymous	c.C445T/p.L149F	D	3.47
20	Likely pathogenic	PHIP	chr6	79650578	rs182783944	0.001 0	Nonsynonymous	c.G5298A/p.M1766I	D	5.92
21	VUS	MCHR1	chr22	41077832	rs190547628	0.007 4	Nonsynonymous	c.G1169A/p.R390H	D	5.40
22	Pathogenic	MC4R	chr18	58039062	rs878909905	Novel	Stopgain	c.G521A/p.W174X	D	5.85
23	VUS	SH2B1	chr16	28883185	rs200463987	0.005 1	Nonsynonymous	c.T386C/p.M129T	DW	5.14
24	Pathogenic	ADCY3	chr2	25042876	rs750100505	0.000 1	Nonsynonymous	c.G3363C/p.K1121N	DS	3.81
	VUS	PHIP	chr6	79655019	rs769344926	0.000 1	Nonsynonymous	c.A4826C/p.Q1609P	B	4.77

Sample ID	ACMG	Gene	Chromosome	Position	dbSNP	MAF in EAS	SNV class	DNA/AA change	Degree of damage	GERP score
1	Pathogenic	NTRK2	chr9	87635191	rs367769334	Novel	Nonsynonymous	c.C2195T/p.T732M	DVS	6.16
2	Likely pathogenic	MCHR1	chr22	41077612	rs182594063	0.001 0	Nonsynonymous	c.C949T/p.R317W	DS	4.19
3	VUS	MCHR1	chr22	41077832	rs190547628	0.007 4	Nonsynonymous	c.G1169A/p.R390H	D	5.40
4	VUS	SH2B1	chr16	28878040	‒	Novel	Nonsynonymous	c.G625A/p.V209I	B	-1.84
5	Pathogenic	AGRP	chr16	67516606	rs199927717	0.001 0	Nonsynonymous	c.G332A/p.R111H	DS	6.17
6	VUS	SH2B1	chr16	28883185	rs200463987	0.005 1	Nonsynonymous	c.T386C/p.M129T	DW	5.14
7	VUS	KSR2	chr12	118199252	‒	Novel	Nonsynonymous	c.C463A/p.P155T	B	2.72
8	Likely pathogenic	LEP	chr7	127894628	‒	Novel	Nonsynonymous	c.G316A/p.D106N	D	3.86
9	Pathogenic	LEPR	chr1	66038032	‒	Novel	Nonsynonymous	c.T394C/p.W132R	DS	4.17
10	Pathogenic	LEPR	chr1	66038032	‒	Novel	Nonsynonymous	c.T394C/p.W132R	DS	4.17
11	VUS	ADCY3	chr2	25050847	rs78678013	0.000 6	Nonsynonymous	c.G2356A/p.A786T	DW	4.50
12	Pathogenic	PHIP	chr6	79655966	‒	Novel	Nonsynonymous	c.A4382G/p.K1461R	D	6.17
13	Pathogenic	MC3R	chr20	54824110	‒	Novel	Nonsynonymous	c.T211C/p.S71P	D	4.00
14	Pathogenic	SH2B1	chr16	28877614	rs781063312	Novel	Nonsynonymous	c.C199T/p.R67C	DS	4.71
	Pathogenic	SH2B1	chr16	28878223	rs561413284	0.001 9	Nonsynonymous	c.C808T/p.R270W	DS	3.96
15	Likely pathogenic	MCHR1	chr22	41077283	rs188147970	0.003 0	Nonsynonymous	c.C620T/p.A207V	D	5.02
16	VUS	BDNF	chr11	27679861	‒	Novel	Nonsynonymous	c.A251G/p.N84S	B	-9.56
17	VUS	SH2B1	chr16	28883185	rs200463987	0.005 1	Nonsynonymous	c.T386C/p.M129T	DW	5.14
18	Pathogenic	PCSK1	chr5	95748060	rs773564429	Novel	Nonsynonymous	c.C844T/p.R282W	DVS	0.38
19	Pathogenic	SH2B1	chr16	28877860	‒	Novel	Nonsynonymous	c.C445T/p.L149F	D	3.47
20	Likely pathogenic	PHIP	chr6	79650578	rs182783944	0.001 0	Nonsynonymous	c.G5298A/p.M1766I	D	5.92
21	VUS	MCHR1	chr22	41077832	rs190547628	0.007 4	Nonsynonymous	c.G1169A/p.R390H	D	5.40
22	Pathogenic	MC4R	chr18	58039062	rs878909905	Novel	Stopgain	c.G521A/p.W174X	D	5.85
23	VUS	SH2B1	chr16	28883185	rs200463987	0.005 1	Nonsynonymous	c.T386C/p.M129T	DW	5.14
24	Pathogenic	ADCY3	chr2	25042876	rs750100505	0.000 1	Nonsynonymous	c.G3363C/p.K1121N	DS	3.81
	VUS	PHIP	chr6	79655019	rs769344926	0.000 1	Nonsynonymous	c.A4826C/p.Q1609P	B	4.77

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利用全外显子测序在肥胖人群中筛查致病突变

Screening for pathogenic variants in obese cohort using whole-exome sequencing

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Gene	Protein	Inheritance
ADCY3	adenylate cyclase 3	AR
AGRP	agouti-related peptide	AD/AR
BDNF	brain-derived neurotrophic factor	AD
KSR2	kinase suppressor of Ras 2	AD
LEP	leptin	AR
LEPR	leptin receptor	AR
MC3R	melanocortin 3 receptor	AD
MC4R	melanocortin 4 receptor	AD/AR
MCHR1	melanin concentrating hormone receptor 1	AD
MRAP2	melanocortin receptor accessory protein 2	AD
NTRK2	neurotrophic receptor tyrosine kinase 2	AD
PCSK1	proprotein convertase subtilisin/kexin type 1	AR
PHIP	pleckstrin homology domain interacting protein	AD
POMC	proopiomelanocortin	AD/AR
SH2B1	SH2B adaptor protein 1	AD
SIM1	SIM bHLH transcription factor 1	AR