PDF(Pubmed)
Abstract：
Insufficient thyroid hormone production in newborns is referred to as congenital hypothyroidism. Multinodular goiter (MNG), characterized by an enlarged thyroid gland with multiple nodules, is usually seen in adults and is recognized as a separate disorder from congenital hypothyroidism. Here we performed a linkage analysis of a family with both nongoitrous congenital hypothyroidism and MNG and identified a signal at 15q26.1. Follow-up analyses with whole-genome sequencing and genetic screening in congenital hypothyroidism and MNG cohorts showed that changes in a noncoding TTTG microsatellite on 15q26.1 were frequently observed in congenital hypothyroidism (137 in 989) and MNG (3 in 33) compared with controls (3 in 38,722). Characterization of the noncoding variants with epigenomic data and in vitro experiments suggested that the microsatellite is located in a thyroid-specific transcriptional repressor, and its activity is disrupted by the variants. Collectively, we presented genetic evidence linking nongoitrous congenital hypothyroidism and MNG, providing unique insights into thyroid abnormalities.
摘要：
新生儿甲状腺激素产生不足被称为先天性甲状腺功能减退症。多结节性甲状腺肿(MNG),以甲状腺肿大伴多个结节为特征，通常见于成人，被认为是先天性甲状腺功能减退症的一种独立疾病。在这里，我们对一个患有非甲状腺肿性先天性甲状腺功能减退症和MNG的家庭进行了连锁分析，并在15q26.1确定了一个信号。在先天性甲状腺功能减退症和MNG队列中进行的全基因组测序和遗传筛查的后续分析表明，与对照组相比，先天性甲状腺功能减退症（989中的137个）和MNG（33中的3个）在15q26.1上经常观察到非编码TTTG微卫星的变化（38,722中的3个）。通过表观基因组数据和体外实验对非编码变体的表征表明，微卫星位于甲状腺特异性转录阻遏物中，其活性被变异体破坏。总的来说，我们提供了非甲状腺肿性先天性甲状腺功能减退症和MNG的遗传证据，提供对甲状腺异常的独特见解。
