Medical Genetic Department, the Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Clinical Laboratory, Medical College of Qingdao University, Qingdao, China.
Endocrine. 2021 Apr;72(1):147-156. doi: 10.1007/s12020-020-02437-8. Epub 2020 Aug 15.
Mutations in DUOX2 are the frequent cause of congenital hypothyroidism (CH), a common neonatal metabolic disorder characterized by great phenotypic variability. CH can be traditionally subclassified into two subtypes: thyroid dysgenesis (TD) and thyroid dyshormonogenesis. The objectives of this study were to analyze the genetic data of two familial CH cases, to elucidate the pathogenesis from the perspective of genetics and to review and summarize the previous findings.
Targeted regions sequencing (TRS) technology covering all exons and intron-exon boundaries of 35 known and potential CH-related candidate target genes in combination with Sanger sequencing were performed to identify the likely pathogenic mutations of the six patients with familial CH.
In family 1, two DUOX2 missense mutations, namely, c.1060C>T/p.R354W in exon 10 and c.3200C>T/p.S1067L in exon 25, were found. Patient 1 (P1), P2 and P3 were transient CH (TCH) patients with eutopic thyroid glands of normal size and function. In family 2, only the mutation c.3200C>T/p.S1067L was identified. P4, P5, and P6 were diagnosed with permanent CH (PCH), which requires lifelong levothyroxine (L-T4) treatment. Furthermore, both P4 and P5 harbored properly located thyroid glands, whereas P6 had a mildly reduced gland. P1, P3, P6, and other family members carrying monoallelic or biallelic DUOX2 mutations showed no obvious abnormal clinical symptoms or signs, while P2, P4, and P5 showed umbilical hernias.
The present study suggests that the phenotypic features resulting from DUOX2 mutations vary greatly. The p.R354W and p.S1067L alterations or the combination of the two alterations in DUOX2 are probably only predisposing to CH and DUOX2 may be involved in the morphogenesis of the human thyroid gland. Simultaneously, the compensation of DUOX1 for the loss of DUOX2, undetectable pathogenic mutations, the effects of environmental factors, epigenetic mechanisms and the involvement of multiple genes cannot be excluded in the explanation of these genetic results.
DUOX2 基因突变是先天性甲状腺功能减退症（CH）的常见原因，CH 是一种常见的新生儿代谢紊乱，其表型具有很大的变异性。CH 传统上可分为两种亚型：甲状腺发育不全（TD）和甲状腺激素生成障碍。本研究的目的是分析两个家族性 CH 病例的遗传数据，从遗传学角度阐明发病机制，并回顾和总结以往的发现。
采用靶向区域测序（TRS）技术，对 35 个已知和潜在的 CH 相关候选靶基因的所有外显子和内含子-外显子边界进行检测，结合 Sanger 测序，对 6 例家族性 CH 患者的可能致病突变进行鉴定。
在家族 1 中，发现了两个 DUOX2 错义突变，即第 10 外显子中的 c.1060C>T/p.R354W 和第 25 外显子中的 c.3200C>T/p.S1067L。患者 1（P1）、P2 和 P3 为暂时性 CH（TCH）患者，甲状腺大小和功能正常。在家族 2 中，仅发现 c.3200C>T/p.S1067L 突变。P4、P5 和 P6 被诊断为永久性 CH（PCH），需要终身左甲状腺素（L-T4）治疗。此外，P4 和 P5 的甲状腺位置正常，而 P6 的甲状腺略小。携带单等位基因或双等位基因 DUOX2 突变的 P1、P3、P6 和其他家族成员无明显异常临床症状或体征，而 P2、P4 和 P5 则存在脐疝。
本研究表明，DUOX2 突变导致的表型特征差异很大。DUOX2 中的 p.R354W 和 p.S1067L 改变或两者的组合可能仅导致 CH，DUOX2 可能参与了人类甲状腺的形态发生。同时，不能排除 DUOX1 对 DUOX2 缺失的补偿、未检测到的致病性突变、环境因素的影响、表观遗传机制以及多个基因的参与可以解释这些遗传结果。
