表观遗传失调已成为神经发育障碍(NDDs)的重要病因机制。表观遗传调节因子的致病变异可削弱组蛋白翻译后修饰的沉积,导致神经发育过程中时空基因表达异常。男性特异性致死(MSL)复合物是基因表达的主要多亚基表观遗传调节剂,负责组蛋白4赖氨酸16乙酰化(H4K16ac)。使用外显子组测序,在这里,我们确定了一个由25名个体组成的队列,这些个体在MSL复杂成员MSL2中具有杂合的从头变异。MSL2变异与NDD表型相关,包括全球发育迟缓,智力残疾,低张力,和运动问题,如协调问题,喂养困难,和步态紊乱。畸形和行为和/或精神疾病,包括自闭症谱系障碍,在较小程度上,癫痫发作,结缔组织疾病的迹象,睡眠障碍,视力问题,和其他器官异常,在受影响的个体中观察到。作为一种分子生物标记,已经建立了敏感和特异性的DNA甲基化表标签.源自我们队列的三个成员的诱导多能干细胞(iPSC)表现出降低的MSL2水平。值得注意的是,而MSL复合体的另外两个成员(MOF和MSL3)中的NDD相关变体导致H4K16ac减少,全局H4K16ac水平在具有MSL2变体的iPSC中没有变化。无论如何,MSL2变体改变了MSL2靶标在iPSC中的表达以及在它们分化为早期胚层时的表达。我们的研究将MSL2相关疾病定义为具有明显临床特征的NDD,一种特定的血液DNA表观标记,和一个独特的,与其他MSL复合物相关疾病相比,MSL2特异性分子病因。
Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders.