Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam University Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada.
Int J Mol Sci. 2023 Sep 18;24(18):14240. doi: 10.3390/ijms241814240.
(Jumonji, AT-rich interactive domain 2) haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. It is characterized by intellectual disability, developmental delay, autistic features, behavior abnormalities, cognitive impairment, hypotonia, and dysmorphic features. acts as a transcriptional repressor protein that is involved in the regulation of histone methyltransferase complexes. plays a role in the epigenetic machinery, and the associated syndrome has an identified DNA methylation episignature derived from sequence variants and intragenic deletions involving . For this study, our aim was to determine whether patients with larger deletions spanning beyond present a similar DNA methylation episignature and to define the critical region involved in aberrant DNA methylation in 6p22-p24 microdeletions. We examined the DNA methylation profiles of peripheral blood from 56 control subjects, 13 patients with (likely) pathogenic variants or patients carrying copy number variants, and three patients with VUS variants. The analysis showed a distinct and strong differentiation between patients with (likely) pathogenic variants, both sequence and copy number, and controls. Using the identified episignature, we developed a binary model to classify patients with the -neurodevelopmental syndrome. DNA methylation analysis indicated that is the driver gene for aberrant DNA methylation observed in 6p22-p24 microdeletions. In addition, we performed analysis of functional correlation of the genome-wide methylation profile with the DNA methylation profiles of 56 additional neurodevelopmental disorders. To conclude, we refined the critical region for the presence of the episignature in 6p22-p24 microdeletions and provide insight into the functional changes in the epigenome observed when regulation by is lost.
（富含精氨酸的转录因子 JUMONJI，AT 结构域 2）单倍剂量不足与一种具有明显临床特征的神经发育综合征相关。其特征为智力残疾、发育迟缓、自闭症特征、行为异常、认知障碍、肌张力低下和发育异常。 作为一种转录抑制蛋白，参与组蛋白甲基转移酶复合物的调节。 发挥着表观遗传机制的作用，相关综合征具有由序列变异和涉及 的基因内缺失引起的可识别的 DNA 甲基化表观遗传特征。在这项研究中，我们的目的是确定跨越 的较大缺失的患者是否存在类似的 DNA 甲基化表观遗传特征，并确定 6p22-p24 微缺失中涉及异常 DNA 甲基化的关键区域。我们检测了 56 名对照、13 名携带（可能）致病性 变异或携带拷贝数变异的患者以及 3 名携带 VUS 变异的患者的外周血 DNA 甲基化谱。分析表明，（可能）致病性变异患者，无论是序列变异还是拷贝数变异，与对照组之间存在明显且强烈的分化。使用鉴定出的表观遗传特征，我们开发了一个二进制模型来对患有 -神经发育综合征的患者进行分类。DNA 甲基化分析表明， 是 6p22-p24 微缺失中观察到的异常 DNA 甲基化的驱动基因。此外，我们还对 基因组范围内的甲基化谱与 56 种额外神经发育障碍的 DNA 甲基化谱之间的功能相关性进行了分析。总之，我们对 6p22-p24 微缺失中 存在表观遗传特征的关键区域进行了细化，并提供了对失去 调节时观察到的表观基因组功能变化的深入了解。
