已有研究表明HDAC8基因突变与Cornelia de Lange综合征（CdLS）的发病有关，但其分子机制尚不清楚。课题组先前采用全外显子组测序和Sanger测序技术对两例来源于不同家系的CdLS患者进行基因检测，发现患者HDAC8基因分别存在一个未被报道的错义突变c.806T>G（p.I269R）和c.113G>A（p.A38V），生物信息学软件预测结果提示其具有致病性。针对HDAC8基因c.806T>G（p.I269R）突变的功能研究结果表明该突变能够显著降低HDAC8蛋白的酶活性。本课题将继续研究另一个新突变的功能，同时构建iPSC疾病模型，探索突变对CdLS患者骨形成的影响及其机制，这不仅能为患者的遗传学病因确诊提供有力证据，还有助于阐明CdLS的发病机制，为以后的治疗提供理论基础。

The HDAC8 gene mutations have been reported to be associated with the occurrence of Cornelia de Lange syndrome (CdLS), but the molecular mechanism has not been elucidated. We recently adopted whole-exome sequencing and Sanger sequencing technologies to analyze genetic mutations in two CdLS patients from different families, and found that the two patients carried an unreported missense mutation (c.806T>G, p.I269R and c.113G>A, p.A38V) of HDAC8 gene, respectively. The prediction results based on bioinformatics software indicated that the two genetic mutations had pathogenicity. The result of functional study of HDAC8 c.806T>G mutation showed that the genetic mutation significantly reduced the enzymatic activity of HDAC8 protein. The project will continue to study the function of the other new mutation, and construct an induced pluripotent stem cell (iPSC) model of CdLS to explore the effect and influence mechanism of the genetic mutations on bone formation. The study will not only provide strong evidence for genetic diagnosis of the present patients, but also be helpful to elucidate the pathogenesis of CdLS, which provides a theoretical basis for the future treatment.