Objective: To preliminarily investigate the relationship between stimulatory G protein α subunit (GNAS) and thyroid hormone receptor α (THRA) gene mutations and clinical phenotypes in children with congenital hypothyroidism (CH).
Methods: A total of 70 children with CH diagnosed by neonatal screening were enrolled. Their peripheral blood samples were collected to extract genomic DNA. GNAS and THRA genes were screened for mutations using next-generation sequencing. Bioinformatics software was used to analyze the pathogenicity of gene mutations.
Results: Of the 70 children with CH, nine missense mutations (three known mutations and six novel mutations) in the GNAS gene were detected in three patients (4%), and one gene polymorphism, c.508A>G(p.I170V), in the THRA gene was detected in four patients. The analysis results of bioinformatics software and ACMG/AMP guidelines showed that the two GNAS gene mutations [c.301C>T(p.R101C) and c.334G>A(p.E112K)] were more likely to be pathogenic. Three children with GNAS gene mutations showed different degrees of hypothyroidism.
Conclusions: GNAS gene mutations are related to the development of CH, and children with CH have different clinical manifestations. THRA gene mutations may not be associated with CH.
目的: 对70例先天性甲状腺功能减退症（CH）患儿的刺激性G蛋白α亚基（GNAS）基因和甲状腺素受体α（THRA）基因进行二代测序分析，并初步探讨GNAS和THRA基因突变型与CH患儿的临床表现型之间的关系。
方法: 选取70例通过新生儿筛查确诊为CH的患儿，采集外周血并进行DNA样本提取，利用二代测序技术对GNAS和THRA基因进行突变筛查，利用生物信息学软件分析基因突变的致病性。
结果: 70例CH患儿中，3例患儿（4%）检出9种GNAS基因的错义突变（包括3种已知基因突变和6种新突变），4例患儿检出同1种THRA基因多态c.508A > G（p.I170V）。经过生物信息学软件预测和ACMG/AMP指南分析发现2种GNAS基因突变[c.301C > T（p.R101C）、c.334G > A（p.E112K）]致病的可能性大。3例携带GNAS基因突变的患儿存在不同程度的甲状腺功能低下表现。
结论: GNAS基因突变与CH的发病有关，患儿的临床表现存在较大的异质性；THRA基因突变可能与CH的发病无相关性。