Journal of Shanghai Jiao Tong University (Medical Science) >

2023 , Vol. 43 >Issue 7: 882 - 889

DOI: https://doi.org/10.3969/j.issn.1674-8115.2023.07.010

Clinical research

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

  • Jinghui WANG ,
  • Hong ZHANG ,
  • Rong ZHANG ,
  • Danfeng PENG ,
  • Hairong YU ,
  • Xianghui CHEN ,
  • Ye XUAN ,
  • Cheng HU ,
  • Yunjuan GU
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  • 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
GU Yunjuan, E-mail: desette@ntu.edu.cn.
HU Cheng, E-mail: alfaedhc@sjtu.edu.cn

Received date: 2023-02-17

  Accepted date: 2023-06-30

  Online published: 2023-07-28

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)

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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

Cite this article

Jinghui WANG , Hong ZHANG , Rong ZHANG , Danfeng PENG , Hairong YU , Xianghui CHEN , Ye XUAN , Cheng HU , Yunjuan GU . 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 . DOI: 10.3969/j.issn.1674-8115.2023.07.010

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