Nature genetics · 2024
Functional variants in a TTTG microsatellite on 15q26.1 cause familial nonautoimmune thyroid abnormalities.
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Narumi Satoshi, Nagasaki Keisuke, Kiriya Mitsuo, Uehara Erika, Akiba Kazuhisa, Tanase-Nakao Kanako, Shimura Kazuhiro, Abe Kiyomi, Sugisawa Chiho, Ishii Tomohiro, Miyako Kenichi, Hasegawa Yukihiro, Maruo Yoshihiro, Muroya Koji, Watanabe Natsuko, Nishihara Eijun, Ito Yuka, Kogai Takahiko, Kameyama Kaori, Nakabayashi Kazuhiko, Hata Kenichiro, Fukami Maki, Shima Hirohito, Kikuchi Atsuo, Takayama Jun, Tamiya Gen, Hasegawa Tomonobu
Аннотация
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.