title: Next-generation sequencing analysis of TSHR in 384 Chinese subclinical congenital hypothyroidism (CH) and CH patients.
abstract: BACKGROUND
  Defects in the human TSHR gene are reported to be one of the causes of CH due to thyroid dysgenesis, the purpose of this study was to examine the TSHR mutation spectrum and prevalence in congenital hypothyroidism (CH) and subclinical congenital hypothyroidism (SCH) patients in the Guangxi Zhuang Autonomous Region of China and to evaluate the genotype-phenotype correlations.
  
  
  METHODS
  Blood samples were collected from 384 patients including 240 CH and 144 SCH patients in Guangxi, China. Genomic DNA was extracted from peripheral blood leukocytes. All exons of the 11 known CH associated genes including TSHR together with their exon-intron boundaries were screened by next-generation sequencing (NGS).
  
  
  RESULTS
  NGS analysis of TSHR revealed nine different variants in ten individuals. Six (4.2%) of 144 patients with SCH were found to harbor monoallelic TSHR variants. Four (1.6%) of 240 patients with CH harbored TSHR variants combined with another monoallelic mutation in either DUOX2 or TG gene. The present study identified five novel variants c.1838A>G (p.Y613C), c.1576G>A (p.A526T), c.2087T>G (p.F696C), c.1631G>A (p.G544E) and c.2051C>A (p.A684D) in TSHR, seven known pathogenic variants c.1349G>A (p.R450H), c.326G>A (p.R109Q), c.2066T>G (p.V689G) and c.2272G>A (p.E758K) in TSHR, IVS3+2T>G in TG, and c.1588A>T (p.K530X) and c.2635G>A (p.E879K) in DUOX2. The previously reported hotspot mutation p.R450H was found in only one SCH patient.
  
  
  CONCLUSIONS
  The prevalence of TSHR mutations was 1.6% in CH patients and 4.2% in SCH patients in Guangxi Zhuang Autonomous Region of China. Monoallelic TSHR pathogenic variants were associated with SCH, while TSHR pathogenic variants combined with monoallelic mutations in DUOX2 or TG gene might contribute to CH. Our study expands the TSHR mutation spectrum and provides the best estimation of mutation rate for SCH and CH patients in this Chinese population.
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Chunyun
authors.initials: C
authors.lastname: Fu
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Luo
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Qifei
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Xuyun
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Jiasun
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Shujie
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Rongyu
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Jingsi
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, United States.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
authors.affiliation: GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wei
authors.affiliation: GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Dahua
authors.initials: D
authors.lastname: Meng
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
authors.forename: Baoheng
authors.initials: B
authors.lastname: Gui
authors.affiliation: Medical Science Laboratory, Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou 545000, People's Republic of China.
authors.forename: Zhangqin
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China. Electronic address: fanxin602@163.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China. Electronic address: chenshaoke123@163.com.
authors.forename: Shaoke
authors.initials: S
authors.lastname: Chen
mesh_terms: D002681:China; D019295:Computational Biology; D003409:Congenital Hypothyroidism / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D004247:DNA / Q000097:blood / Q000235:genetics; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D011989:Receptors, Thyrotropin / Q000097:blood / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012984:Software
chemical_list: D011989:Receptors, Thyrotropin; D004247:DNA
keywords: Chinese population; Gene mutations; Next-generation sequencing; Subclinical congenital hypothyroidism; TSH receptor gene (TSHR)