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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.