High frequency of mutations in 'dyshormonogenesis genes' in severe congenital hypothyroidism,PLOS ONE

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High frequency of mutations in 'dyshormonogenesis genes' in severe congenital hypothyroidism
PLOS ONE ( IF 2.9 ) Pub Date : 2018-09-21 , DOI: 10.1371/journal.pone.0204323
Nina Makretskaya ₁ , Olga Bezlepkina ₁ , Anna Kolodkina ₁ , Alexey Kiyaev ₂ , Evgeny V Vasilyev ₁ , Vasily Petrov ₁ , Svetlana Kalinenkova ₃ , Oleg Malievsky ₄ , Ivan I Dedov ₁ , Anatoly Tiulpakov ₁

Affiliation

Objective

Results of the screening of disease causative mutations in congenital hypothyroidism (CH) vary significantly, depending on the sequence strategy, patients’ inclusion criteria and bioinformatics. The objective was to study the molecular basis of severe congenital hypothyroidism, using the next generation sequencing (NGS) and the recent guidelines for assessment of sequence variants.

Design

243 patients with CH (TSH levels at neonatal screening or retesting greater than 90 mU/l) and 56 control subjects were included in the study.

Methods

A custom NGS panel targeting 12 CH causative genes was used for sequencing. The sequence variants were rated according to American College of Medical Genetics and Genomics (ACMG) guidelines.

Results

In total, 48 pathogenic, 7 likely pathogenic and 57 variants of uncertain significance were identified in 92/243 patients (37.9%), while 4 variants of uncertain significance were found in 4/56 control subjects (7.1%). 13.1% (12/92) of the cases showed variants in ‘thyroid dysgenesis’ (TD) genes: TSHR, n = 6; NKX2-1, n = 2; NKX2-5, n = 1; PAX8, n = 3. The variants in ‘dyshormonogenesis’ (DH) genes were found in 84.8% (78/92) of cases: TPO, n = 30; DUOX2, n = 24; TG, n = 8; SLC5A5, n = 3; SLC26A4, n = 6; IYD, n = 1. 8 patients showed oligonenic variants. The majority of variants identified in DH genes were monoallelic.

Conclusions

In contrast to earlier studies demonstrating the predominance of TD in severe CH, the majority of variants identified in our study were in DH genes. A large proportion of monoallelic variants detected among DH genes suggests that non-mendelian mechanisms may play a role in the development of CH.

中文翻译：

严重先天性甲状腺功能减退症患者“激素生成异常基因”突变频率较高

客观的

先天性甲状腺功能减退症 (CH) 致病突变的筛查结果差异很大，具体取决于序列策略、患者纳入标准和生物信息学。目的是利用下一代测序 (NGS) 和最近的序列变异评估指南来研究严重先天性甲状腺功能减退症的分子基础。

设计

该研究纳入了 243 名 CH 患者（新生儿筛查或复检时的 TSH 水平大于 90 mU/l）和 56 名对照受试者。

方法

使用针对 12 个 CH 致病基因的定制 NGS panel 进行测序。根据美国医学遗传学和基因组学学院 (ACMG) 指南对序列变异进行评级。

结果

总共，在 92/243 名患者 (37.9%) 中发现了 48 种致病性、7 种可能致病性和 57 种意义不明的变异，而在 4/56 名对照受试者 (7.1%) 中发现了 4 种意义不确定的变异。13.1% (12/92) 的病例显示“甲状腺发育不全”(TD) 基因变异：TSHR，n = 6；NKX2-1，n=2；NKX2-5，n=1；PAX8，n = 3。在 84.8% (78/92) 的病例中发现“激素生成障碍”(DH) 基因变异：TPO，n = 30；DUOX2，n = 24；TG，n=8；SLC5A5，n=3；SLC26A4，n = 6；IYD，n = 1。8 名患者表现出寡聚变异。DH 基因中发现的大多数变异都是单等位基因。