Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.

中文翻译：

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X连锁智力障碍的USP27X变体通过不同的机制破坏蛋白质功能。

伴有智力障碍的神经发育障碍 (ND/ID) 是一组异质性疾病，可导致终身认知和行为缺陷，且无法根治。X 连锁智力障碍障碍 105（XLID105，#300984；OMIM）是一种 ND/ID，由USP27X基因中的半合子变异驱动，该基因编码一种在细胞增殖和神经发育中发挥作用的蛋白去泛素化酶。目前，仅描述了来自两个无关家庭的四名基因诊断个体，且临床数据有限。此外，该疾病的机制尚不清楚。在这里，我们报告了来自 9 个家族的 10 个新 XLID105 个体，并确定了基因变异对 USP27X 蛋白功能的影响。结合临床遗传学、生物信息学、生物化学和细胞生物学方法，我们确定 XLID105 变体通过不同的机制改变 USP27X 蛋白质生物学，包括发育相关的蛋白质-蛋白质相互作用和去泛素化活性的变化。我们的数据更好地定义了 XLID105 的表型谱，并表明 XLID105 是由 USP27X 功能破坏驱动的。了解 XLID105 变异的致病机制将为 USP27X 生物学提供分子洞察，并可能为治疗开发创造潜力。