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.

新生儿甲状腺激素分泌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) 的特点是甲状腺肿大并有多个结节，通常见于成人，被认为是与先天性甲状腺功能减退症不同的一种疾病。在这里，我们对一个同时患有非甲状腺肿先天性甲状腺功能减退症和 MNG 的家族进行了连锁分析，并在 15q26.1 处发现了一个信号。对先天性甲状腺功能减退症和 MNG 队列进行全基因组测序和遗传筛查的后续分析表明，与先天性甲状腺功能减退症（989 例中的 137 例）和 MNG（33 例中的 3 例）相比，15q26.1 上非编码 TTTG 微卫星的变化经常观察到。控制（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抑制子中，并且其活性被变体破坏。总的来说，我们提出了非甲状腺肿先天性甲状腺功能减退症和 MNG 之间联系的遗传证据，为甲状腺异常提供了独特的见解。