通过传统的连锁分析和候选基因测序分析等策略,迄今已有超过3 000种单基因疾病(如囊性纤维化、镰状细胞性贫血等)的遗传病因得以阐明[1],但目前人们仍对约3 500种单基因疾病的致病基因缺乏了解。同时,患者数量及家系过少、疾病外显不完全、疾病遗传异质性及患病个体显著降低的生育能力等因素极大地限制了传统分析策略发现、鉴定疾病基因的能力和效力[2]。虽然每一种单基因疾 So far, the genetic causes of over 3,000 monogenic diseases (such as cystic fibrosis and sickle-cell anemia) have been elucidated by traditional methods such as linkage analysis and candidate gene sequencing [1] Lack of understanding of causative genes of about 3,500 single-gene diseases. At the same time, factors such as the number of patients and families, the incomplete appearance of the disease, the genetic heterogeneity of the disease and the significantly reduced fertility of the affected individual greatly limit the ability and effectiveness of the traditional analysis methods to discover and identify disease genes [2] . Although every single gene disease