Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities
Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities
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DOI：
10.1038/s41431-017-0023-0
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发表时间：
2017-12-01
影响因子：
5.2
通讯作者：
Bjornsson, Hans T.
中科院分区：
文献类型：
--
作者：
Sobreira, Nara;Brucato, Martha;Bjornsson, Hans T.
歌舞伎综合征是由编码组蛋白修饰酶的两个基因中的任何一个的功能变体丧失引起的单基因疾病。我们对27名临床诊断为歌舞伎综合征的先证者进行了靶向测序。其中，12个在两个已知的歌舞伎综合征基因中有致病变异。在2中，我们确定了KMT 2A（错义和剪接位点变异体）的推定功能缺失突变，KMT 2A是一种编码另一种组蛋白修饰酶的基因，以前只与Wiedermann-Steiner综合征相关。虽然歌舞伎综合征是一种组蛋白修饰的疾病，但我们也发现了歌舞伎综合征诊断个体相对于匹配的正常对照的DNA甲基化改变，无论他们是否携带KMT 2A或KMT 2D的变体。此外，我们观察到特征性的DNA甲基化的全局异常，其将具有KMT 2D中的功能缺失变体或KMT 2D或KMT 2A中的错义或剪接位点变体的患者与正常对照区分开。我们的研究结果提供了新的见解基因型表观基因型和表型的关系，并表明组蛋白和DNA甲基化机制暴露的先天性错误的表观遗传装置之间的串扰。
Kabuki syndrome is a monogenic disorder caused by loss of function variants in either of two genes encoding histone-modifying enzymes. We performed targeted sequencing in a cohort of 27 probands with a clinical diagnosis of Kabuki syndrome. Of these, 12 had causative variants in the two known Kabuki syndrome genes. In 2, we identified presumptive loss of function de novo variants in KMT2A (missense and splice site variants), a gene that encodes another histone modifying enzyme previously exclusively associated with Wiedermann-Steiner syndrome. Although Kabuki syndrome is a disorder of histone modification, we also find alterations in DNA methylation among individuals with a Kabuki syndrome diagnosis relative to matched normal controls, regardless of whether they carry a variant in KMT2A or KMT2D or not. Furthermore, we observed characteristic global abnormalities of DNA methylation that distinguished patients with a loss of function variant in KMT2D or missense or splice site variants in either KMT2D or KMT2A from normal controls. Our results provide new insights into the relationship of genotype to epigenotype and phenotype and indicate cross-talk between histone and DNA methylation machineries exposed by inborn errors of the epigenetic apparatus.