Zhu Jitao, Li Wenhui, Yu Sha, Lu Wei, Xu Qiong, Wang Sujuan, Qian Yanyan, Guo Qiufang, Xu Suzhen, Wang Yao, Zhang Ping, Zhao Xuemei, Ni Qi, Liu Renchao, Li Xu, Wu Bingbing, Zhou Shuizhen, Wang Huijun
Center for Molecular Medicine, Pediatrics Research Institute, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Neurology Department, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
Front Pediatr. 2023 Mar 3;11:1091532. doi: 10.3389/fped.2023.1091532. eCollection 2023.
Neurodevelopmental disorders (NDDs) have heterogeneity in both clinical characteristics and genetic factors. is a recently discovered gene associated with a syndromic form of NDDs characterized by hypotonia, ataxia and facial features. In this study, we report twelve unrelated individuals with variants using next-generation sequencing. Five missense variants (four novel variants and one known variant) and seven copy number variations (CNVs) of gene were identified. All of these patients exhibited developmental delay/intellectual disability. Ataxia was observed in 33% (6/9) of the patients, and abnormal muscle tone was observed in 55% (6/11) of the patients. Aberrant MRI reports were noted in 64% (7/11) of the patients. Four novel missense variants were all located in the DNA-binding domain. The pathogenicity of these variants was validated by experiments. We found that the subcellular protein localization of the R152C and F211L mutants was changed, and the distribution pattern of the R163G mutant was changed from even to granular. Luciferase assay results showed that the four EBF3 mutants' transcriptional activities were all significantly decreased ( < 0.01). Our study further expanded the gene mutation spectrum of EBF3-related NDD.
神经发育障碍（NDDs）在临床特征和遗传因素方面均具有异质性。EBF3是最近发现的一个与以肌张力减退、共济失调和面部特征为特征的综合征形式的NDDs相关的基因。在本研究中，我们使用下一代测序报告了12名携带EBF3变异的无血缘关系个体。鉴定出了5个错义变异（4个新变异和1个已知变异）以及7个EBF3基因的拷贝数变异（CNV）。所有这些患者均表现出发育迟缓/智力残疾。33%（6/9）的患者观察到共济失调，55%（6/11）的患者观察到肌张力异常。64%（7/11）的患者MRI报告异常。4个新的错义变异均位于DNA结合域。这些变异的致病性通过实验得到验证。我们发现R152C和F211L突变体的亚细胞蛋白定位发生了变化，R163G突变体的分布模式从均匀变为颗粒状。荧光素酶检测结果显示，4个EBF3突变体的转录活性均显著降低（P < 0.01）。我们的研究进一步扩展了EBF3相关NDD的基因突变谱。
