{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:58:30Z","timestamp":1791845910190,"version":"4.3.4"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"2","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,2]]},"abstract":"<jats:sec>\n<jats:title>Objective<\/jats:title>\n<jats:p>Biallelic <jats:italic>TSHR<\/jats:italic> mutations cause congenital hypothyroidism (CH). Serum TSH levels of monoallelic mutation carriers range from normal to mildly elevated, and thus the size of its effect remains unclear. The objectives were to examine the association between monoallelic <jats:italic>TSHR<\/jats:italic> mutations and positivity at newborn screening (NBS) for CH, and to test whether the association was modified by another genetic factor.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Subjects and methods<\/jats:title>\n<jats:p>We enrolled 395 patients that had a positive result in NBS and sequenced <jats:italic>TSHR.<\/jats:italic> Monoallelic <jats:italic>TSHR<\/jats:italic> mutation carriers were further sequenced for <jats:italic>DUOX2<\/jats:italic>. Molecular functions of the mutations were verified <jats:italic>in vitro<\/jats:italic>. The frequency of the mutations in the study subjects was compared with a theoretical value in the Japanese general population. Odds ratio (OR) for NBS positivity associated with the mutation was calculated. Using Bayes\u2019 theorem, we estimated a posterior probability of NBS positivity given the mutation.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Twenty-six monoallelic <jats:italic>TSHR<\/jats:italic> mutation carriers were found. Four out of the 26 also had a monoallelic <jats:italic>DUOX2<\/jats:italic> mutation (double heterozygotes). The frequencies of monoallelic <jats:italic>TSHR<\/jats:italic> mutation carriers (6.6%) and double heterozygotes (1.0%) were significantly higher than those in the general population (0.58% and 0.0087%, respectively). OR for NBS positivity of having a monoallelic <jats:italic>TSHR<\/jats:italic> mutation or being a double heterozygote was 12.0 or 117.9, respectively. Posterior probability of NBS positivity was 0.38% in monoallelic <jats:italic>TSHR<\/jats:italic> mutation carriers and 3.8% in double heterozygotes.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Monoallelic <jats:italic>TSHR<\/jats:italic> mutations are significantly associated with NBS positivity, and the association is further strengthened by the coexistence of monoallelic <jats:italic>DUOX2<\/jats:italic> mutations.<\/jats:p>\n<\/jats:sec>","DOI":"10.1530\/eje-16-1049","type":"journal-article","created":{"date-parts":[[2017,11,2]],"date-time":"2017-11-02T00:30:42Z","timestamp":1509582642000},"page":"137-144","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":26,"title":["Association between monoallelic TSHR mutations and congenital hypothyroidism: a statistical approach"],"prefix":"10.1093","volume":"178","author":[{"given":"Kiyomi","family":"Abe","sequence":"first","affiliation":[{"name":"1Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Narumi","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan"},{"name":"2Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayuko S.","family":"Suwanai","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Adachi","sequence":"additional","affiliation":[{"name":"3Department of Endocrinology and Metabolism, Kanagawa Children\u2019s Medical Center, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Muroya","sequence":"additional","affiliation":[{"name":"3Department of Endocrinology and Metabolism, Kanagawa Children\u2019s Medical Center, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumi","family":"Asakura","sequence":"additional","affiliation":[{"name":"3Department of Endocrinology and Metabolism, Kanagawa Children\u2019s Medical Center, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Nagasaki","sequence":"additional","affiliation":[{"name":"4Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Abe","sequence":"additional","affiliation":[{"name":"5Center for Clinical Research, Keio University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomonobu","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"1Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","reference":[{"key":"ref211","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1002\/jcu.10234","article-title":"Simple new technique for sonographic measurement of the thyroid in neonates and small children","volume":"32","year":"2004","journal-title":"Journal of Clinical Ultrasound"},{"key":"ref281","doi-asserted-by":"crossref","first-page":"6320","DOI":"10.1210\/jc.2003-032185","article-title":"Altered thyroid and adrenal function in children born at term and preterm, small for gestational age","volume":"89","year":"2004","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref181","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1086\/301871","article-title":"Missense mutations in disease genes: a Bayesian approach to evaluate causality","volume":"62","year":"1998","journal-title":"American Journal of Human Genetics"},{"key":"ref241","doi-asserted-by":"crossref","first-page":"30","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","year":"2016","journal-title":"Clinica Chimica Acta"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"4187","DOI":"10.1210\/jc.2009-0618","article-title":"Thyrotropin-stimulating hormone receptor gene analysis in pediatric patients with non-autoimmune subclinical hypothyroidism","volume":"94","year":"2009","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref141","first-page":"657","article-title":"Hypothyroidism caused by the combination of two heterozygous mutations: one in the TSH receptor gene the other in the DUOX2 gene","volume":"28","year":"2015","journal-title":"Journal of Pediatric Endocrinology and Metabolism"},{"key":"ref271","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/S0022-3476(05)80385-3","article-title":"Age-related changes in serum free thyroxine during childhood and adolescence","volume":"123","year":"1993","journal-title":"Journal of Pediatrics"},{"key":"ref231","first-page":"214","article-title":"Delayed onset congenital hypothyroidism in a patient with DUOX2 mutations and maternal iodine excess","volume":"161A","year":"2013","journal-title":"American Journal of Medical Genetics Part A"},{"key":"ref221","doi-asserted-by":"crossref","first-page":"561","DOI":"10.3343\/alm.2016.36.6.561","article-title":"A population-based genomic study of inherited metabolic diseases detected through newborn screening","volume":"36","year":"2016","journal-title":"Annals of Laboratory Medicine"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.mce.2010.01.008","article-title":"Genetics and phenomics of hypothyroidism due to TSH resistance","volume":"322","year":"2010","journal-title":"Molecular and Cellular Endocrinology"},{"key":"ref91","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1210\/jc.2008-1767","article-title":"TSHR mutations as a cause of congenital hypothyroidism in Japan: a population-based genetic epidemiology study","volume":"94","year":"2009","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref191","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1210\/jc.2009-2373","article-title":"Transcription factor mutations and congenital hypothyroidism: systematic genetic screening of a population-based cohort of Japanese patients","volume":"95","year":"2010","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref01","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1159\/000182549","article-title":"Comparison of epidemiological data on congenital hypothyroidism in Europe with those of other parts in the world","volume":"38","year":"1992","journal-title":"Hormone Research"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1210\/jc.2007-0366","article-title":"A familial thyrotropin (TSH) receptor mutation provides in vivo evidence that the inositol phosphates\/Ca2+ cascade mediates TSH action on thyroid hormone synthesis","volume":"92","year":"2007","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref251","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1055\/s-0042-112224","article-title":"The prevalence, clinical, and molecular characteristics of congenital hypothyroidism caused by DUOX2 mutations: a population-based cohort study in Guangzhou","volume":"48","year":"2016","journal-title":"Hormone and Metabolic Research"},{"key":"ref121","doi-asserted-by":"crossref","first-page":"4025","DOI":"10.1210\/jc.2005-0572","article-title":"Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds: clinical characterization and exclusion of candidate loci","volume":"90","year":"2005","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"3018","DOI":"10.1172\/JCI119497","article-title":"Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland","volume":"99","year":"1997","journal-title":"Journal of Clinical Investigation"},{"key":"ref71","doi-asserted-by":"crossref","first-page":"2549","DOI":"10.1210\/jcem.87.6.8536","article-title":"Germline mutations of TSH receptor gene as cause of non-autoimmune subclinical hypothyroidism","volume":"87","year":"2002","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref171","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1093\/aje\/153.12.1222","article-title":"Commentary: practical advantages of Bayesian analysis of epidemiologic data","volume":"153","year":"2001","journal-title":"American Journal of Epidemiology"},{"key":"ref261","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3343\/alm.2016.36.2.145","article-title":"DUOX2 mutations are frequently associated with congenital hypothyroidism in the Korean population","volume":"36","year":"2016","journal-title":"Annals of Laboratory Medicine"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1056\/NEJM199501193320305","article-title":"Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene","volume":"332","year":"1995","journal-title":"New England Journal of Medicine"},{"key":"ref101","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.1210\/jc.2009-0375","article-title":"Subclinical hypothyroidism in children and adolescents: a wide range of clinical, biochemical, and genetic factors involved","volume":"94","year":"2009","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"ref151","volume-title":"Bayesian Methods for Data Analysis.","year":"2008"},{"key":"ref201","doi-asserted-by":"crossref","first-page":"O55","DOI":"10.1186\/1687-9856-2013-S1-O55","article-title":"A study of the etiology of transient congenital hypothyroidism in Niigata Prefecture, Japan","volume":"2013","year":"2013","journal-title":"International Journal of Pediatric Endocrinology"},{"key":"ref81","doi-asserted-by":"publisher","first-page":"201297","DOI":"10.1210\/jc.2011-1938","article-title":"TSH receptor genetic alterations with variable signaling impairment in a large series of children with non - autoimmune isolated hyperthyrotropinemia of and","journal-title":"Journal Clinical Endocrinology Metabolism"},{"key":"ref111","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.1093\/hmg\/ddi329","article-title":"Intracellular entrapment of wild-type TSH receptor by oligomerization with mutants linked to dominant TSH resistance","volume":"14","year":"2005","journal-title":"Human Molecular Genetics"},{"key":"ref131","doi-asserted-by":"publisher","first-page":"201196","DOI":"10.1210\/jc.2011-1573","article-title":"Molecular basis of thyroid dyshormonogenesis : genetic screening in population - based Japanese patients of and","journal-title":"Journal Clinical Endocrinology Metabolism"},{"key":"ref161","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1093\/jnci\/89.3.227","article-title":"Probability of carrying a mutation of Breast-Ovarian Cancer Gene BRCA1 based on family history","volume":"89","year":"1997","journal-title":"Journal of the National Cancer 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