X染色体USP9X基因编码一种去泛素化酶,该酶参与胎儿和神经元发育过程中的蛋白质更新和TGF-β信号传导。女性的USP9X变异主要与功能完全丧失(LOF)等位基因有关,导致神经发育迟缓和智力残疾,以及广泛的先天性异常。相比之下,男性的USP9X错义变异通常会导致部分而不是完全的LOF,特别影响神经元迁移和发育。男性的USP9X变异与智力障碍有关,行为障碍,全球发育迟缓,说话延迟,和中枢神经系统结构缺陷。几乎所有患者都发现面部畸形。
■我们报道了一个意大利男孩出现畸形的病例,智力残疾,大脑结构异常,先天性心脏病.使用下一代测序分析,我们在USP9X基因中鉴定出一个半合子从头变异体(c.5470A>G,p.Met1824Val),这在文献中从未报道过。
■我们提供了有关男性USP9X变体的现有文献的概述,为了进一步扩大男性限制性X连锁智力低下综合征的基因型和表型格局。我们的发现证实了USP9X变体参与神经元发育,并证实了新型USP9X变体与先天性心脏畸形之间的可能关联。
UNASSIGNED: The X-chromosomal
USP9X gene encodes a deubiquitylating enzyme involved in protein turnover and TGF-β signaling during fetal and neuronal development.
USP9X variants in females are primarily associated with complete loss-of-function (LOF) alleles, leading to neurodevelopmental delay and intellectual disability, as well as a wide range of congenital anomalies. In contrast, USP9X missense variants in males often result in partial rather than complete LOF, specifically affecting neuronal migration and development. USP9X variants in males are associated with intellectual disability, behavioral disorders, global developmental delay, speech delay, and structural CNS defects. Facial dysmorphisms are found in almost all patients.
UNASSIGNED: We report the case of an Italian boy presenting dysmorphism, intellectual disability, structural brain anomalies, and congenital heart disease. Using next-generation sequencing analysis, we identified a hemizygous de novo variant in the
USP9X gene (c.5470A>G, p.Met1824Val) that was never reported in the literature.
UNASSIGNED: We provide an overview of the available literature on
USP9X variants in males, in order to further expand the genotypic and phenotypic landscape of male-restricted X-linked mental retardation syndrome. Our findings confirm the involvement of USP9X variants in neuronal development and corroborate the possible association between the novel
USP9X variant and congenital heart malformation.