High Frequency of <b><i>DUOX2</i></b> Mutations in Transient or Permanent Congenital Hypothyroidism with Eutopic Thyroid Glands

<b><i>Background/Aims:</i></b> This study aimed to clarify the frequency, phenotypes, and molecular spectrum of <i>DUOX2</i>,<i> TPO</i>, <i>TSHR, </i>and <i>TG</i> mutations in patients with congenital hypothyroidism (CH) with enlarged or normal-sized eutopic thyroid glands. <b><i>Methods:</i></b> The study cohort included 43 subjects from 41 unrelated families who had CH with eutopic thyroid glands. Mutation analyses of <i>DUOX2</i>,<i> TPO</i>, and<i> TSHR</i> were performed. The functional capacities of novel missense variants of <i>DUOX2</i> were verified by measuring H₂O₂ generation in vitro. <b><i>Results:</i></b> Of the 43 subjects, 23 (53.5%) had sequence variants in at least one gene. Twelve different <i>DUOX2</i> variants, including seven novel variants, were identified in 20 subjects. A functional analysis of the <i>DUOX2</i> variants revealed that most variants, other than p.G206V and p.H678R, caused a significant reduction in H₂O₂ generation. Therefore, 15 subjects harbored functionally deleterious <i>DUOX2</i> variants. Of these, 5 subjects had transient CH, and 10 were found to have permanent CH. Sequence variants in <i>TSHR</i> were identified in 5 subjects. One of the 43 subjects (2.3%) had sequence variants in two different genes. <b><i>Conclusions:</i></b><i>DUOX2</i> variants are a relatively common cause of CH with normal-sized or enlarged eutopic thyroid glands. Variable phenotypes were associated with partial loss of the functional activity of <i>DUOX2</i> variants.