Yamaguchi Takeshi, Nakamura Akie, Nakayama Kanako, Hishimura Nozomi, Morikawa Shuntaro, Ishizu Katsura, Tajima Toshihiro
Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Kid's Forest Pediatrics & Endocrinology, Sapporo, Japan.
J Clin Endocrinol Metab. 2020 Aug 1;105(8). doi: 10.1210/clinem/dgaa308.
Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder; however, its molecular etiology remains poorly understood.
We performed genetic analysis of 24 causative genes using next-generation sequencing in 167 CH cases, comprising 57 dyshormonogenesis (DH), 32 dysgenesis (TD) and 78 undiagnosed. The pathogenicity of variants was assessed by the American College of Medical Genetics guidelines, inheritance pattern, and published evidence. Furthermore, we compared the oligogenic groups and monogenic groups to examine the correlation between variant dosage and severity.
We identified variants in 66.5% cases (111/167) and 15 genes, DUOX2, TSHR, PAX8, TG, TPO, DUOXA2, JAG1, GLIS3, DUOX1, IYD, SLC26A4, SLC5A5, SECISBP2, DIO1, and DIO3. Biallelic variants were identified in 12.6% (21/167), oligogenic in 18.0% (30/167), and monogenic in 35.9% (60/167); however, 68.5% of variants were classified as variant of unknown significance (VUS). Further examinations showed that 3 out of 32 cases with TD (9.4%) had pathogenic variants (2 of TSHR and 1 of TPO), and 8 out of 57 cases with DH (14.0%) (7 of DUOX2, 1 of TG) had pathogenic variants. In addition, TSH levels at the first visit were significantly higher in the oligogenic group than in the monogenic group.
The detection rate of pathogenic variants in Japanese CH was similar to that previously reported. Moreover, oligogenic cases were likely to be more severe than monogenic cases, suggesting that CH may exhibit a gene dosage effect. Further analysis of VUS pathogenicity is required to clarify the molecular basis of CH.
先天性甲状腺功能减退症（CH）是最常见的新生儿内分泌疾病；然而，其分子病因仍知之甚少。
我们对167例CH病例进行了下一代测序，对24个致病基因进行了基因分析，其中包括57例激素合成障碍（DH）、32例甲状腺发育不全（TD）和78例未确诊病例。根据美国医学遗传学学会的指南、遗传模式和已发表的证据评估变异的致病性。此外，我们比较了寡基因组和单基因组，以检查变异剂量与严重程度之间的相关性。
我们在66.5%的病例（111/167）中鉴定出变异，涉及15个基因，即DUOX2、TSHR、PAX8、TG、TPO、DUOXA2、JAG1、GLIS3、DUOX1、IYD、SLC26A4、SLC5A5、SECISBP2、DIO1和DIO3。双等位基因变异在12.6%（21/167）的病例中被鉴定出，寡基因变异在18.0%（30/167）的病例中被鉴定出，单基因变异在35.9%（60/167）的病例中被鉴定出；然而，68.5%的变异被分类为意义未明的变异（VUS）。进一步检查显示，32例TD病例中有3例（9.4%）有致病变异（TSHR 2例，TPO 1例），57例DH病例中有8例（14.0%）（DUOX2 7例，TG 1例）有致病变异。此外，寡基因组首次就诊时促甲状腺激素水平显著高于单基因组。
日本CH病例中致病变异的检出率与先前报道的相似。此外，寡基因病例可能比单基因病例更严重，这表明CH可能表现出基因剂量效应。需要进一步分析VUS的致病性以阐明CH的分子基础。
