遗传变异是先天性甲低（CH）的重要致病因素，且与CH患者的病理分类、表型特征及临床转归等密切相关，但CH相关遗传变异复杂多样且致病机制不明，成为阻碍CH精准防治的瓶颈。项目组前期发现在中国CH人群中GNAS基因突变高发，但相关分子流行病学数据、基因型-表型关系谱及致病机制未见报道。预实验发现GNAS新颖突变p.I103T导致cAMP的生成减少，提示该突变可能通过干扰cAMP信号通路的转导能力，降低细胞对TSH的敏感性，从而导致CH发生。课题组拟以CH人群为研究对象，描绘CH人群GNAS遗传变异谱，探索GNAS遗传变异的流行病学特征和遗传模式，同时以p.I103T突变作为切入点研究GNAS突变的致病机制，为CH的精准防治和遗传学干预提供理论依据。

Genetic variation, which is closely related to the pathological classification, phenotypic characteristics and clinical outcomes of congenital hypothyroidism(CH), is an important pathogenic factor of CH. Complexity and diversity of CH-related genetic variation and unclear pathogenic mechanism hinder the precise prevention and treatment of CH. Our previous studies found that mutation of GNAS was high-frequency in Chinese CH population, but molecular epidemiological data and genotype-phenotype relationship of GNAS variation were not studied, and the pathogenesis was unknown. Our previous studies also found that novel mutation of GNAS, p.I103T, reduced the production of cAMP. It implied that mutation of p.I103T may reduce the TSH sensitivity by disturbing cAMP signaling pathway. We will study genetic variation, epidemiological characteristics and genetic model of GNAS variation in CH population. We will also study the pathogenesis of GNAS mutation by studying the p.I103T mutation. Our study may provide theoretical basis for the precise prevention, treatment and genetic intervention of CH.