{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T03:15:00Z","timestamp":1791947700130,"version":"4.3.4"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T00:00:00Z","timestamp":1630627200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"\n Background<\/jats:title>\n The molecular etiology and the genotype\u2013phenotype correlation of congenital hypothyroidism (CH) remain unclear.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We performed genetic analysis in 42 newborns with CH using whole-exome sequencing. Patients were divided into a single-gene group and a multi-gene group according to the number of affected genes, or divided into a monoallelic group, a biallelic group, and an oligogenic group according to the pattern of the detected variants. The clinical characteristics were compared between groups.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Thyroid dysgenesis (TD) was observed in 10 patients and goiter in 5 patients, whereas 27 patients had normal-sized gland-in-situ (GIS). We identified 58 variants in five genes in 29 patients. The genes with the most frequent variants were\n DUOX2<\/jats:italic>\n (70.7%), followed by\n TSHR<\/jats:italic>\n (12.1%),\n DUOXA2<\/jats:italic>\n (10.3%), and\n TPO<\/jats:italic>\n (5.2%). Variants in the genes causing dyshormonogenesis (DH) were more common than those in the genes causing TD (87.9%\n versus<\/jats:italic>\n 12.1%). Among the patients with detected variants, 26 (89.7%) were harboring a single gene variant (single-gene group), which include 22 patients harboring biallelic variants (biallelic group) and four patients harboring monoallelic variants (monoallelic group). Three (10.3%) patients harbored variants in two or three genes (multi-gene group or oligogenic group). Compared with the single-gene group, the levothyroxine (L-T4) dose at 1 year of age was higher in the multi-gene group (\n p<\/jats:italic>\n = 0.018). A controllable reduction in the L-T4 dose was observed in 25% of patients in the monoallelic group and 59.1% of patients in the biallelic group; however, no patients with such reduction in the L-T4 dose were observed in the oligogenic group.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Patients with normal-sized GIS accounted for the majority of our cohort. Genetic defects in the genes causing DH were more common than those in the genes causing TD, with biallelic variants in\n DUOX2<\/jats:italic>\n being dominant. DH might be the leading pathophysiology of CH in Chinese individuals.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fendo.2021.705773","type":"journal-article","created":{"date-parts":[[2021,9,4]],"date-time":"2021-09-04T06:47:40Z","timestamp":1630738060000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Genetic and Phenotypic Characteristics of Congenital Hypothyroidism in a Chinese Cohort"],"prefix":"10.3389","volume":"12","author":[{"given":"Wei","family":"Long","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruen","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaiyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/1750-1172-5-17","article-title":"Congenital Hypothyroidism","volume":"5","author":"Rastogi","year":"2010","journal-title":"Orphanet J Rare Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s42000-020-00267-x","article-title":"Genetics of Primary Congenital Hypothyroidism-a Review","volume":"20","author":"Kostopoulou","year":"2021","journal-title":"Horm (Athens)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13627","article-title":"Molecular Defects in Thyroid Dysgenesis","volume":"97","author":"Mio","year":"2020","journal-title":"Clin Genet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"R297","DOI":"10.1530\/EJE-18-0383","article-title":"Diagnosis of Endocrine Disease: Congenital Hypothyroidism: Update and Perspectives","volume":"179","author":"Peters","year":"2018","journal-title":"Eur J Endocrinol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"62","DOI":"10.17352\/pjbrd.000006","article-title":"Advances and Perspectives in Genetics of Congenital Thyroid Disorders Associated With Thyroglobulin Gene Mutations","volume":"1","author":"Targovnik","year":"2016","journal-title":"Open J Biol Sci"},{"key":"B6","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1007\/s12020-021-02646-9","article-title":"New Genetics in Congenital Hypothyroidism","volume":"71","author":"Stoupa","year":"2021","journal-title":"Endocrine"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.7863\/jum.2011.30.7.895","article-title":"Sonographic Measurement of Thyroid Volumes in Healthy Chinese Infants Aged 0 to 12 Months","volume":"30","author":"Yao","year":"2011","journal-title":"J Ultrasound Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30","article-title":"Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-1573","article-title":"Molecular Basis of Thyroid Dyshormonogenesis: Genetic Screening in Population-Based Japanese Patients","volume":"96","author":"Narumi","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3275\/8973","article-title":"The Molecular Causes of Thyroid Dysgenesis: A Systematic Review","volume":"36","author":"Nettore","year":"2013","journal-title":"J Endocrinol Invest"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.21037\/atm-20-7165","article-title":"Genotype and Phenotype Correlation in a Cohort of Chinese Congenital Hypothyroidism Patients With DUOX2 Mutations","volume":"8","author":"Zheng","year":"2020","journal-title":"Ann Transl Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqab043","article-title":"Dual Oxidase (DUOX) System Genes Defects in Children With Congenital Hypothyroidism","volume":"162","author":"Wang","year":"2021","journal-title":"Endocrinology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1530\/EC-20-0411","article-title":"DUOX2 Variants Are a Frequent Cause of Congenital Primary Hypothyroidism in Thai Patients","volume":"9","author":"Sorapipatcharoen","year":"2020","journal-title":"Endocr Connect"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-17-1017","article-title":"The Genetic Characteristics of Congenital Hypothyroidism in China by Comprehensive Screening of 21 Candidate Genes","volume":"178","author":"Sun","year":"2018","journal-title":"Eur J Endocrinol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa308","article-title":"Targeted Next-Generation Sequencing for Congenital Hypothyroidism With Positive Neonatal TSH Screening","volume":"105","author":"Yamaguchi","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2016.04.019","article-title":"Next-Generation Sequencing Analysis of DUOX2 in 192 Chinese Subclinical Congenital Hypothyroidism (SCH) and CH Patients","volume":"458","author":"Fu","year":"2016","journal-title":"Clin Chim Acta"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1055\/s-0042-112224","article-title":"Clinical, and Molecular Characteristics of Congenital Hypothyroidism Caused by DUOX2 Mutations: A Population-Based Cohort Study in Guangzhou","volume":"48","author":"Tan","year":"2016","journal-title":"Horm Metab Res"},{"key":"B18","first-page":"73","article-title":"Genetic Evaluation of Congenital Hypothyroidism With Gland in Situ Using Targeted Exome Sequencing","volume":"51","author":"Shin","year":"2021","journal-title":"Ann Clin Lab Sci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-0856","article-title":"Transient Congenital Hypothyroidism Caused by Biallelic Mutations of the Dual Oxidase 2 Gene in Japanese Patients Detected by a Neonatal Screening Program","volume":"93","author":"Maruo","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-15-0959","article-title":"Natural Course of Congenital Hypothyroidism by Dual Oxidase 2 Mutations From the Neonatal Period Through Puberty","volume":"174","author":"Maruo","year":"2016","journal-title":"Eur J Endocrinol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3343\/alm.2016.36.2.145","article-title":"DUOX2 Mutations Are Frequently Associated With Congenital Hypothyroidism in the Korean Population","volume":"36","author":"Park","year":"2016","journal-title":"Ann Lab Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s13023-017-0575-7","article-title":"Exome Sequencing Identifies SLC26A4, GJB2, SCARB2 and DUOX2 Mutations in 2 Siblings With Pendred Syndrome in a Malaysian Family","volume":"12","author":"Chow","year":"2017","journal-title":"Orphanet J Rare Dis"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1210\/me.2007-0018","article-title":"Missense Mutations of Dual Oxidase 2 (DUOX2) Implicated in Congenital Hypothyroidism Have Impaired Trafficking in Cells Reconstituted With DUOX2 Maturation Factor","volume":"21","author":"Grasberger","year":"2007","journal-title":"Mol Endocrinol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1056\/NEJMoa012752","article-title":"Inactivating Mutations in the Gene for Thyroid Oxidase 2 (THOX2) and Congenital Hypothyroidism","volume":"347","author":"Moreno","year":"2002","journal-title":"N Engl J Med"},{"key":"B25","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.mce.2010.01.029","article-title":"Defects of Thyroidal Hydrogen Peroxide Generation in Congenital Hypothyroidism","volume":"322","author":"Grasberger","year":"2010","journal-title":"Mol Cell Endocrinol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.5546\/aap.2017.e162","article-title":"Transient Congenital Hypothyroidism Due to Biallelic Defects of DUOX2 Gene. Two Clinical Cases","volume":"115","author":"Enacan","year":"2017","journal-title":"Arch Argent Pediatr"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1111\/cen.12469","article-title":"Genotypes and Phenotypes of Congenital Goitre and Hypothyroidism Caused by Mutations in Dual Oxidase 2 Genes","volume":"81","author":"Wang","year":"2014","journal-title":"Clin Endocrinol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2016.0469","article-title":"DUOX2 Gene Mutation Manifesting as Resistance to Thyrotropin Phenotype","volume":"27","author":"Srichomkwun","year":"2017","journal-title":"Thyroid"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2017-00832","article-title":"DUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Gland","volume":"102","author":"Kizys","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"B30","doi-asserted-by":"publisher","first-page":"6808517","DOI":"10.1155\/2020\/6808517","article-title":"Complicated Relationship Between Genetic Mutations and Phenotypic Characteristics in Transient and Permanent Congenital Hypothyroidism: Analysis of Pooled Literature Data","volume":"2020","author":"Long","year":"2020","journal-title":"Int J Endocrinol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx145","article-title":"A Frequent Oligogenic Involvement in Congenital Hypothyroidism","volume":"26","author":"de Filippis","year":"2017","journal-title":"Hum Mol Genet"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-1879","article-title":"Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-In-Situ","volume":"101","author":"Nicholas","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.EJ18-0156","article-title":"Targeted Next-Generation Sequencing of Thirteen Causative Genes in Chinese Patients With Congenital Hypothyroidism","volume":"65","author":"Long","year":"2018","journal-title":"Endocr J"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx145","article-title":"A Frequent Oligogenic Involvement in Congenital Hypothyroidism","volume":"26","author":"de Filippis","year":"2017","journal-title":"Hum Mol Genet"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2018.05.002","article-title":"Genetics and Management of Congenital Hypothyroidism","volume":"32","author":"Persani","year":"2018","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.4274\/jcrpe.2380","article-title":"A Novel C.554+5C>T Mutation in the DUOXA2 Gene Combined With P.R885Q Mutation in the DUOX2 Gene Causing Congenital Hypothyroidism","volume":"8","author":"Zheng","year":"2016","journal-title":"J Clin Res Pediatr Endocrinol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-06-0709","article-title":"Screening for Mutations in Transcription Factors in a Czech Cohort of 170 Patients With Congenital and Early-Onset Hypothyroidism: Identification of a Novel PAX8 Mutation in Dominantly Inherited Early-Onset Non-Autoimmune Hypothyroidism","volume":"156","author":"Al Taji","year":"2007","journal-title":"Eur J Endocrinol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.545339","article-title":"High Diagnostic Yield of Targeted Next-Generation Sequencing in a Cohort of Patients With Congenital Hypothyroidism Due to Dyshormonogenesis","volume":"11","author":"Stoupa","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-18-0379","article-title":"Genetics in Endocrinology: Genetic Diagnosis of Endocrine Diseases by NGS: Novel Scenarios and Unpredictable Results and Risks","volume":"179","author":"Luca","year":"2018","journal-title":"Eur J Endocrinol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa454","article-title":"Unraveling the Genetics of Congenital Hypothyroidism: Challenges and Opportunities","volume":"105","author":"Wassner","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"B41","doi-asserted-by":"publisher","first-page":"297","DOI":"10.3892\/mmr.2020.11078","article-title":"Mutation Spectrum Analysis of 29 Causative Genes in 43 Chinese Patients With Congenital Hypothyroidism","volume":"22","author":"Wang","year":"2020","journal-title":"Mol Med Rep"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.705773\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,4]],"date-time":"2021-09-04T06:47:45Z","timestamp":1630738065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.705773\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,3]]},"references-count":41,"alternative-id":["10.3389\/fendo.2021.705773"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.705773","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,3]]},"article-number":"705773"}}