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Until now, the gene mutations have been reported associated with TD can only account for 5% cases, suggesting the genetic heterogeneity of the pathology. Nicotinamide nucleotide transhydrogenase (<jats:italic>NNT<\/jats:italic>) plays a crucial role in regulating redox homeostasis, patients carrying <jats:italic>NNT<\/jats:italic> mutations have been described with a clinical phenotype of hypothyroidism. As TD risk is increased in the context of several syndromes and redox homeostasis is vital for thyroid development and function, <jats:italic>NNT<\/jats:italic> might be a candidate gene involved in syndromic TD. Therefore, we performed target sequencing (TS) in 289 TD patients for causative mutations in <jats:italic>NNT<\/jats:italic> and conducted functional analysis of the gene mutations. TS and Sanger sequence were used to screen the novel mutations. For functional analysis, we performed western blot, measurement of NADPH\/NADP<jats:sub>total<\/jats:sub> and H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> generation, cell proliferation, and wounding healing assay. As a result, three presumably pathogenic mutations (c.811G\u2009&gt;\u2009A, p.Ala271Ser; c.2078G\u2009&gt;\u2009A, p.Arg693His; and c.2581G\u2009&gt;\u2009A, p.Val861Met) in <jats:italic>NNT<\/jats:italic> had been identified. Our results showed the damaging effect of <jats:italic>NNT<\/jats:italic> mutations on stability and catalytic activity of proteins and redox balance of cells. In conclusion, our findings provided novel insights into the role of the <jats:italic>NNT<\/jats:italic> isotype in thyroid physiopathology and broaden the spectrum of pathogenic genes associated with TD. However, the pathogenic mechanism of <jats:italic>NNT<\/jats:italic> in TD is still need to be investigated in further study.<\/jats:p>","DOI":"10.1002\/ajmg.a.62493","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T07:43:35Z","timestamp":1632210215000},"page":"89-98","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Nicotinamide nucleotide transhydrogenase mutation analysis in Chinese patients with thyroid dysgenesis"],"prefix":"10.1002","volume":"188","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1290-7120","authenticated-orcid":false,"given":"Miaomiao","family":"Li","sequence":"first","affiliation":[{"name":"The Affiliated Hospital of Qingdao University Medical Genetic Department, Prenatal Diagnosis Center  Qingdao China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weibing","family":"Tian","sequence":"additional","affiliation":[{"name":"Weifang 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