CTCF deletion syndrome: clinical features and epigenetic delineation
CTCF deletion syndrome: clinical features and epigenetic delineation
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DOI：
10.1136/jmedgenet-2017-104854
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发表时间：
2017-12-01
影响因子：
4
通讯作者：
Saitoh, Shinji
中科院分区：
文献类型：
--
作者：
Hori, Ikumi;Kawamura, Rie;Saitoh, Shinji
背景：CTCF杂合性突变在具有不同临床特征的患者中已有报道，包括智力残疾。然而，这种表型背后的确切发病机制仍不清楚，部分原因是CTCFs的不同功能。我们对两例CTCF微缺失的患者进行了广泛的临床和遗传学研究。方法我们进行了遗传学检查，包括全面的X染色体失活调查和印迹基因座和全基因组DNA甲基化分析。结果两名患者的临床特征与先前报道的相似，表明CTCF单倍体充足是微缺失综合征的主要决定因素。尽管CTCF存在单倍性不足，但X染色体失活是正常的。印迹基因座DNA甲基化正常，但CTCF结合位点高甲基化，其中PRKCZ和FGFR2被确定为候选基因。结论本研究证实CTCF单倍体缺失导致不同的临床特征，CTCF微缺失可导致可识别的CTCF缺失综合征。CTCF结合位点上的DNA甲基化紊乱，而不是印迹基因座上的DNA甲基化，可能是该综合征的发病机制。
Background Heterozygous mutations in CTCF have been reported in patients with distinct clinical features including intellectual disability. However, the precise pathomechanism underlying the phenotype remains to be uncovered, partly because of the diverse function of CTCF. Here we describe extensive clinical and genetic investigation for two patients with a microdeletion encompassing CTCF.Methods We performed genetic examination including comprehensive investigation of X chromosome inactivation and DNA methylation profiling at imprinted loci and genome-wide.Results Two patients showed comparable clinical features to those in a previous report, indicating that haploin sufficiency of CTCF was the major determinant of the microdeletion syndrome. Despite the haploinsufficiency of CTCF, X chromosome inactivation was normal. DNA methylation at imprinted loci was normal, but hypermethylation at CTCF binding sites was demonstrated, of which PRKCZ and FGFR2 were identified as candidate genes.Conclusions This study confirms that haploinsufficiency of CTCF causes distinct clinical features, and that a microdeletion encompassing CTCF could cause a recognisable CTCF deletion syndrome. Perturbed DNA methylation at CTCF binding sites, not at imprinted loci, may underlie the pathomechanism of the syndrome.