A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3
A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3
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DOI：
10.1016/j.ajhg.2016.11.018
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发表时间：
2017-01-05
影响因子：
9.8
通讯作者：
Malicdan, May Christine V.
中科院分区：
文献类型：
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作者：
Chao, Hsiao-Tuan;Davids, Mariska;Malicdan, May Christine V.
早期B细胞因子3 （EBF3）是高度进化保守的Collier/Olf/EBF （COE）转录因子家族的一员。先前对无脊椎动物和脊椎动物的研究表明，EBF3同源物对生存至关重要，功能丧失突变与一系列神经系统发育缺陷有关，包括神经元发育和迁移的扰动。有趣的是，aristaless相关同源盒（ARX），一种含有同源盒的转录因子，对神经系统发育的调节至关重要，可通过转录抑制EBF3的表达。然而，与EBF3相关的人类神经发育障碍尚未报道。在这里，我们描述了三个受整体发育迟缓、智力残疾和表达性语言障碍影响的个体，并携带EBF3的新生变异。这些个体的相关特征包括先天性张力低下、结构性中枢神经系统畸形、共济失调和泌尿生殖系统异常。新生变异影响锌指基序中对DNA结合至关重要的单个保守残基，并且在苍蝇模型中是有害的。我们的研究结果表明，EBF3的突变可引起遗传性神经发育综合征，并提示EBF3功能的丧失可能介导arx相关疾病（包括智力残疾、生殖器异常和结构性中枢神经系统畸形）共享的神经表型子集。
Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.