CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum
CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum
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DOI：
10.1038/s41436-019-0585-z
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发表时间：
2019-12-01
影响因子：
8.8
通讯作者：
Zweier, Christiane
中科院分区：
文献类型：
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作者：
Konrad, Enrico D. H.;Nardini, Niels;Zweier, Christiane
目的：之前在 7 名患有神经发育障碍 (NDD) 的个体中报道了染色质组织者 CTCF 的致病性变异。方法：通过国际合作，我们收集了 39 名具有 CTCF 变异的受试者的数据。我们对血液样本中的 RNA 进行了转录组分析，并利用果蝇研究了 Ctcf 剂量改变对神经系统发育和功能的影响。结果：我们队列中的个体携带 2 个缺失、8 个可能的基因破坏、2 个剪接位点和 20 个不同的错义变异，其中大多数是从头变异。两例为家族性病例。相关表型的严重程度各不相同，从轻度发育迟缓或智商正常到严重智力障碍。喂养困难和行为异常很常见，还观察到了不同的其他发现，包括生长受限和心脏缺陷。对 5 个个体进行 RNA 测序，发现了 3828 个失调基因，这些基因富含已知的 NDD 基因和转录调控等生物过程。果蝇中 Ctcf 剂量的改变导致总体神经功能受损以及学习和记忆缺陷。结论：我们显着拓宽了 CTCF 相关 NDD 的突变和临床谱。我们的数据通过识别失调基因揭示了 CTCF 的功能作用，并表明 Ctcf 改变会导致果蝇神经系统缺陷。
Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD).Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function.Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits.Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.