遗传变异是重要的致病因素。除了经典的孟德尔遗传病，遗传学家往往无法凭单个基因的罕见突变来诊断病例。存在表型差异、一因多效性等热点问题，流行用多基因遗传、与环境互作等来部分地解答。申请人发表在新英格兰医学杂志的研究揭示TBX6基因的罕见突变联合常见多态共同致病的复合遗传机理，用基因剂量模型解释单个基因的不同遗传变异如何导致个体间表型差异。为深入探索TBX6变异及其致出生缺陷的剂量机理，本项目拟针对先天性脊柱侧凸、肾脏发育不全、缪勒管发育不全等TBX6相关疾病，鉴定致病性遗传变异；利用基因组编辑技术、细胞和小鼠模型研究TBX6变异在转录、剪接、蛋白等三个层面的剂量变化，鉴定TBX6剂量下降在脊柱、肾脏和缪勒管发育中的致畸阈值，建立TBX6剂量与临床表型之间的相关性规律，并探索其内在分子机制。本项目将揭示基因剂量机理在遗传病中的重要作用，帮助解释表型与基因型的复杂关系，促进疾病的诊断和遗传咨询。

Genetic variants play important roles in pathogenesis of human diseases. Different from the Mendelian disorders, geneticists failed frequently in resolving complex diseases by using information of only a single gene. Phenotypic variability and pleiotropism are the major concerns of clinical genetics, which can be partially explained by the polygenic model and/or gene-environment interaction. In 2015, the applicant published his work in New England Journal of Medicine and reported the compound inheritance of rare TBX6 mutations and a common polymorphism in the same gene in manifesting human diseases. This work suggested that the phenotypic variance between individuals can also be explained by the dosage effect of a single gene. To further investigate TBX6 gene variants and their dosage effects in human birth defects, we will conduct the genetic analysis of TBX6 in congenital scoliosis, congenital kidney anomalies and Müllerian aplasia. The dosage effects of TBX6 variants will be carefully examined at the levels of transcription, splicing and protein function using the genome editing technology together with the cell and mouse models. The dosage thresholds to manifesting variable clinical phenotypes will also be determined. This project will reveal the correlation of TBX6 gene dosage and clinical severity, and uncover the molecular basis of TBX6 in human development. This work will shed light on the gene dosage effect in human genetic disorders, help elucidate genotype-phenotype correlations, and facilitate molecular diagnosis and genetic counseling.