ASXL基因家族包括ASXL1、ASXL2及ASXL3三个成员，研究表明ASXL1和ASXL2是参与调节心脏发育的重要基因，而ASXL3基因在心脏发育中的作用仍未知。ASXL3基因截断突变可导致常染色体显性遗传性Bainbridge-Ropers综合征（神经发育症状为主）。本项目前期研究：（1）应用外显子测序在一个生育三例先心病患儿家系中发现患者均携带ASXL3基因复合杂合错义突变；（2）在一例散发先心病例中发现ASXL3基因复合杂合错义突变；（3）构建了ASXL3基因突变C57BL/6小鼠模型。至今已报道与人类疾病相关的ASXL基因突变均为截断突变（无义突变或移码突变），复合杂合或纯合错义突变尚无报道。本项目从细胞、分子、动物水平研究ASXL3基因在心脏发育及维持心脏功能中的作用，探索其在PcG-H3K/H2A通路中的调控作用，从而阐明该基因突变导致常染色体隐性遗传性先心病的发病机制。

ASXL family genes include ASXL1, ASXL2 and ASXL3.Previous studies have shown that ASXL1 and ASXL2 genes are required for normal cardiac development and maintenance of cardiac function. While the function of ASXL3 gene in cardiac development has not been clarifed. Truncating mutations in ASXL3 genes could cause Bainbridge-Ropers syndrome inherited in an autosomal dominant model (characterized by neurodevelopmental symptoms). In our previous study: (1) whole exome sequencing analysis revealed compound heterozygous missense mutations in the ASXL3 gene from a family with three children manifesting congenital heart defects (CHD). (2)Compound heterozygous missense mutations in ASXL3 gene were further identified in a sporadic patient with CHD. (3) C57BL/6 mouse model with ASXL3 gene mutations were established. ASXL3 gene mutations recorded in human diseases were all truncating (nonsense or frameshift) mutations, compound heterozygous or homozygous (missense) mutations has not been reported so far. This project is aimed to study the function of ASXL3 gene in the cardiac development and maintenance of cardiac function by celluar, molecular and animal researches, to explore the regulator mechanism of ASXL3 gene in the PcG-H3K/H2A pathway, and finally to elucidate the pathogenesis of autosomal recessive congenital heart disease caused by ASXL3 gene mutation.