β地中海贫血的临床表型从轻到重差异极大,未经规范化治疗的重型β地贫致死率高。确定影响表型的遗传因素并据此预测个体患重型地贫的可能性对该病的精准诊治意义重大。目前我国尚缺乏对此类因素的系统性分析，也未通过大人群病例队列研究建立相应的风险评估模型。因此，本项目将开展如下研究：1）选取β基因型和临床表型不对应的个体，对选定靶基因采用二代测序发现新的功能性变异，再通过功能分析阐明其调控β/γ/BCL11A基因表达的具体机制。2）在大人群β地贫病例队列中分析1）中发现的新遗传因素、β/α/KLF1基因和调控HbF水平的SNP位点情况，统计学方法量化其遗传贡献度，建立可预测个体患重型地贫风险的评估模型。本项目完成后可加深我们对遗传因素影响β地贫表型效应的认识，提高根据基因型判断表型严重度的准确性，为临床开展针对性的产前诊断和遗传咨询提供可靠的遗传学依据。

Clinical phenotype of β thalassemia encompass a wide spectrum spanning from mild anemia to severe anemia, and the lethality of patients of thalassemia major without systematic treatment is very high. To find the new genetic modifiers which affect phenotypic severity and construct a risk-assessment model for thalassemia major are very useful in precision clinical management. However, which genetic factors affect the phenotype and how much they affect remain confused. Here we want to discover novel functional variants in some target genesin the samples of selected individuals whose phenotype not corresponding to the genotype of β-globin. The influence of these functional variants on the mRNA expression level of the target gene is analyzed. The expression impact of β globin,γ globin and BCL11A proteins caused by the expressed alteration of the target gene are analyzed by functional analysis.According to above results, the molecular mechanism of the new genetic modifiers affect the clincal phenotype of β thalassemia is clarified. Next, a large population β-thalassemia patients were recruited. The genotype of new genetic modifiers, β globin, α globin and KLF1 gene and some SNPs were analyzed to evaluate their genetic contribution towards the clinical phenotype and build a predictive score of severity. The results could be helpful in describe the genotype-phenotype correlations. It will be useful in prenatal diagnosis and genetic counseling of β-thalassemia.