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Abstract：
Intellectual disability (ID), which affects around 2% to 3% of the population, accounts for 0.63% of the overall prevalence of neurodevelopmental disorders (NDD). ID is characterized by limitations in a person\'s intellectual and adaptive functioning, and is caused by pathogenic variants in more than 1000 genes. Here, we report a rare missense variant (c.350T>C; p.(Leu117Ser)) in HACE1 segregating with NDD syndrome with clinical features including ID, epilepsy, spasticity, global developmental delay, and psychomotor impairment in two siblings of a consanguineous Pakistani kindred. HACE1 encodes a HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), which is involved in protein ubiquitination, localization, and cell division. HACE1 is also predicted to interact with several proteins that have been previously implicated in the ID phenotype in humans. The p.(Leu117Ser) variant replaces an evolutionarily conserved residue of HACE1 and is predicted to be deleterious by various in silico algorithms. Previously, eleven protein truncating variants of HACE1 have been reported in individuals with NDD. However, to our knowledge, p.(Leu117Ser) is the second missense variant in HACE1 found in an individual with NDD.
摘要：
智力残疾（ID），影响了大约2%到3%的人口，占神经发育障碍(NDD)总患病率的0.63%。身份证的特点是一个人的智力和适应性功能受到限制，是由1000多个基因的致病变异引起的。这里,我们报告了HACE1中罕见的错义变异（c.350T>C;p。（Leu117Ser）），与NDD综合征分离，临床特征包括ID，癫痫,痉挛,全球发育迟缓，以及巴基斯坦近亲的两个兄弟姐妹的精神运动障碍。HACE1编码HECT结构域和含有E3泛素蛋白连接酶1（HACE1）的锚蛋白重复序列，参与蛋白质泛素化，本地化,和细胞分裂。还预测HACE1与先前与人类ID表型有关的几种蛋白质相互作用。p。（Leu117Ser）变体替换了HACE1的进化上保守的残基，并且被各种计算机模拟算法预测是有害的。以前,已经在患有NDD的个体中报道了HACE1的11种蛋白质截短变体。然而,根据我们的知识，p。（Leu117Ser）是在具有NDD的个体中发现的HACE1中的第二个错义变体。
