Identification of novel Mendelian disorders of the epigenetic machinery (MDEMs)-associated functional mutations and neurodevelopmental disorders
Identification of novel Mendelian disorders of the epigenetic machinery (MDEMs)-associated functional mutations and neurodevelopmental disorders
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DOI：
10.1093/qjmed/hcad005
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发表时间：
2023-05-27
影响因子：
13.3
通讯作者：
Wu, L.
中科院分区：
文献类型：
--
作者：
Li, S.;Li, H.;Wu, L.
背景：表观遗传机制孟德尔障碍（MDEM）是一组新发现的神经发育障碍（NDD）和多种先天性异常，由编码表观遗传机制成分的基因突变引起。许多研究表明，MDEM相关突变可能会破坏染色质状态的平衡并引发发育异常。目的：帮助8个患有NDD的中国家庭获得明确的诊断。方法：在本研究中，我们使用全外显子组测序来诊断8个不相关的中国NDD家庭。我们还通过桑格测序验证了潜在的致病变异，并分析了基因表达的变化以及组蛋白甲基化修饰。结果：鉴定了六个表观遗传机制基因的八个变异，其中六个是新的。六个变异是致病性 (P) 或可能致病 (LP)，而两个新的错义变异（CHD1 中的 c.5113T>C 和 KMT2D 中的 c.10444C>T）被分类为意义不确定的变异 (VUS)。进一步的功能研究证实，CHD1 中的 c.5113T>C 会导致蛋白质水平降低和染色质修饰增加 (H3K27me3)。此外，KMT2D 中的 c.10444C>T 导致 mRNA 转录和染色质修饰 (H3K4me1) 显着减少。根据实验证据，这两种VUS变异可归类为LP。结论：本研究为8个NDD家系提供了明确诊断，扩大了MDEM的突变谱，丰富了表观遗传机制基因变异的发病机制研究。
Background: Mendelian disorders of the epigenetic machinery (MDEMs) are a newly identified group of neurodevelopmental disorders (NDDs) and multiple congenital anomalies caused by mutations in genes encoding components of the epigenetic machinery. Many studies have shown that MDEM-associated mutations may disrupt the balance of chromatin states and trigger dysplasia.Aim: To help eight Chinese families with NDDs acquire a definitive diagnosis.Methods: In this study, we used whole-exome sequencing to diagnose eight unrelated Chinese families with NDDs. We also verified the potential pathogenic variants by Sanger sequencing and analyzed the changes in gene expression along with histone methylation modifications.Results: Eight variants of six epigenetic machinery genes were identified, six of which were novel. Six variants were pathogenic (P) or likely pathogenic (LP), while two novel missense variants (c.5113T>C in CHD1 and c.10444C>T in KMT2D) were classified to be variants of uncertain significance (VUS). Further functional studies verified that c.5113T>C in CHD1 results in decreased protein levels and increased chromatin modifications (H3K27me3). In addition, c.10444C>T in KMT2D led to a significant decrease in mRNA transcription and chromatin modifications (H3K4me1). Based on experimental evidence, these two VUS variants could be classified as LP.Conclusion: This study provided a definitive diagnosis of eight families with NDDs and expanded the mutation spectrum of MDEMs, enriching the pathogenesis study of variants in epigenetic machinery genes.