CorneliadeLange综合征（CdLS）是一种以独特的面部特征为特征的多系统遗传疾病，生长迟缓,和智力残疾，以及各种系统条件。它是由与cohesin复合物相关的基因中的遗传变异引起的。单核苷酸变异是CdLS最著名的遗传原因；然而，拷贝数变异(CNV)显然是该综合征相当大比例病例的基础.NIPBL基因被认为是其中临床相关CNV促成CdLS的基因座。然而,在过去的几年里，已在其他基因如HDAC8、RAD21和SMC1A中鉴定出致病性CNV。这里,我们研究了一个受影响的女孩，该女孩表现出经典的CdLS表型杂合，从头〜32kbp基因内复制影响HDAC8的外显子10。分子分析显示，生理剪接发生了变化，其中包括HDAC8主要转录本的外显子9和10之间的96bp插入。预测异常转录物产生截短的蛋白质，其对活性中心的可接近性受到限制，显示底物进入突变酶的容易性降低。最后,我们得出的结论是，重复是造成患者表型的原因，强调CNVs作为CdLS的分子原因的贡献。
Cornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the best-known genetic cause of CdLS; however, copy number variants (CNVs) clearly underlie a substantial proportion of cases of the syndrome. The NIPBL gene was thought to be the locus within which clinically relevant CNVs contributed to CdLS. However, in the last few years, pathogenic CNVs have been identified in other genes such as
HDAC8, RAD21, and SMC1A. Here, we studied an affected girl presenting with a classic CdLS phenotype heterozygous for a de novo ~32 kbp intragenic duplication affecting exon 10 of
HDAC8. Molecular analyses revealed an alteration in the physiological splicing that included a 96 bp insertion between exons 9 and 10 of the main transcript of
HDAC8. The aberrant transcript was predicted to generate a truncated protein whose accessibility to the active center was restricted, showing reduced ease of substrate entry into the mutated enzyme. Lastly, we conclude that the duplication is responsible for the patient\'s phenotype, highlighting the contribution of CNVs as a molecular cause underlying CdLS.
