Fang Wang1, Chang Liu2, Xiuhua Jia3, Xiangju Liu4, Yinglei Xu5, Shengli Yan2, Xuewen Jia6, Zuzhou Huang7, Shiguo Liu8, Maosheng Gu9. 1. Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China. 2. Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China. 3. Clinic Lab, Linyi Maternal and Children Health's Hospital, Linyi, China. 4. Genetics Diagnostic Lab, Tai'an Maternity and Child Care Hospital, Tai'an 271000, China. 5. Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China. 6. Department of Cardiovascular, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China. 7. Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China. 8. Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China. Electronic address: liushiguo2002@126.com. 9. Genetic Medicine Center, Xuzhou Maternal and Children Health's Hospital, Xuzhou 221009, China. Electronic address: gumaosheng2007@126.com.
Abstract
BACKGROUND: The abnormal expression of certain transcription factors (NKX2.1, FOXE1, NKX2.5, and PAX8) and thyroid stimulating hormone receptor (TSHR) genes has been associated with athyreosis, which is a form of thyroid dysgenesis (TD). We aimed to identify candidate gene mutations in CH patients with athyreosis and to establish the genotype-phenotype correlations in a Chinese population. METHODS: The exons and flanking sequences of NKX2.1, FOXE1, NKX2.5, PAX8, and TSHR were screened by next-generation sequencing and further confirmed by direct Sanger sequencing. The mutation frequencies were calculated and compared against databases. The relationship between genotype and phenotype was also determined. RESULTS: Seven variants were detected in TSHR-p.P52T, p.G132R, p.M164K, p.R450H, p.C700E, p.A522V, and p.R528S. The p. G132R, p. M164K and p. R528S variants were first identified in public databases. Five variants (p.G44D, p.G360V, p.R401Q, p.L418I, and p.E453Q) were found in NKX2.1 and one variant (p.P243T) was detected in FOXE1. In addition, one variant (p.N291I) was found in NKX2.5 and two variants (p.A355V and c.-26G>A) were detected in PAX8. CONCLUSIONS: Our study indicated that TSHR mutations have phenotypic variability and has further expanded the mutation spectrum of TSHR. We also revealed that the rate of NKX2.1, FOXE1, NKX2.5, and PAX8 mutations were low in patients with CH and athyreosis, in contrast to the higher rate of TSHR mutations.
BACKGROUND: The abnormal expression of certain transcription factors (NKX2.1, FOXE1, NKX2.5, and PAX8) and thyroid stimulating hormone receptor (TSHR) genes has been associated with athyreosis, which is a form of thyroid dysgenesis (TD). We aimed to identify candidate gene mutations in CH patients with athyreosis and to establish the genotype-phenotype correlations in a Chinese population. METHODS: The exons and flanking sequences of NKX2.1, FOXE1, NKX2.5, PAX8, and TSHR were screened by next-generation sequencing and further confirmed by direct Sanger sequencing. The mutation frequencies were calculated and compared against databases. The relationship between genotype and phenotype was also determined. RESULTS: Seven variants were detected in TSHR-p.P52T, p.G132R, p.M164K, p.R450H, p.C700E, p.A522V, and p.R528S. The p. G132R, p. M164K and p. R528S variants were first identified in public databases. Five variants (p.G44D, p.G360V, p.R401Q, p.L418I, and p.E453Q) were found in NKX2.1 and one variant (p.P243T) was detected in FOXE1. In addition, one variant (p.N291I) was found in NKX2.5 and two variants (p.A355V and c.-26G>A) were detected in PAX8. CONCLUSIONS: Our study indicated that TSHR mutations have phenotypic variability and has further expanded the mutation spectrum of TSHR. We also revealed that the rate of NKX2.1, FOXE1, NKX2.5, and PAX8 mutations were low in patients with CH and athyreosis, in contrast to the higher rate of TSHR mutations.