KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b^+/−), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.

KDM4B是一种赖氨酸特异性脱甲基酶，对H3K9三/二甲基化（H3K9me3 / 2）修饰的组蛋白具有优先活性。H3K9 tri / di-demethylation是重要的表观遗传机制，负责沉默动物发育和癌症中的基因表达。但是，KDM4B在人类发展中的作用仍然很差。通过国际数据共享，我们收集了一个由9个个体组成的队列，这些个体具有KDM4B中的单等位基因从头或遗传变异。所有表现出畸形特征和整体发育迟缓（GDD）的人，其语言和运动技能受影响最大。三名患者有癫痫病史，四名患者的脑部影像学异常，包括伴有脑积水的call体发育不全，囊性形成，海马异常和多微球菌。在小鼠中，赖氨酸脱甲基酶4B在大脑发育过程中在海马中高水平表达，这是学习和记忆的重要区域。为了了解KDM4B变体如何在人类中导致GDD，我们通过体内杂合小鼠模型（Kdm4b ^+/-）评估了KDM4B破坏对大脑解剖结构和行为的影响。），着重于神经解剖学变化。在突变小鼠中，随着海马齿状回的大小减小，call体的部分发育不全和心室肥大，总脑容量明显减少。该报告证明KDM4B中的变体与GDD /智力障碍和神经解剖缺陷有关。我们的发现表明，KDM4B变异会导致染色质病变，从而拓宽了由表观遗传机制的改变引起的孟德尔疾病的范围。