The defining DNA methylation signature of Kabuki syndrome enables functional assessment of genetic variants of unknown clinical significance
The defining DNA methylation signature of Kabuki syndrome enables functional assessment of genetic variants of unknown clinical significance
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DOI：
10.1080/15592294.2017.1381807
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发表时间：
2017-01-01
期刊：
影响因子：
3.7
通讯作者：
Sadikovic, Bekim
中科院分区：
文献类型：
--
作者：
Aref-Eshghi, Erfan;Schenkel, Laila C.;Sadikovic, Bekim
歌舞伎综合征（KS）是由KMT2D突变引起的，KMT2D是一种参与H3K4甲基化的组蛋白甲基转移酶，H3K4是一种与DNA甲基化相关的组蛋白标记物。对24名KMT 2D致病性突变的KS患者和216名对照的> 450，000个CpG进行分析，鉴定出24个基因组区域，沿着1，504个CpG位点具有显著的DNA甲基化变化，包括许多Hox基因和MYO1F基因。使用最具差异性和显著性的探针和区域，我们开发了“甲基化变体致病性（MVP）评分”，其能够100%敏感和特异地鉴定KS个体，这使用多个公共和内部患者DNA甲基化数据库进行了确认。我们还证明了MVP评分能够准确地重新分类具有明显KS临床特征的受试者中未知意义的变体，使其在分子诊断中具有潜在的用途。这些发现为KS的分子病因学提供了新的见解，并说明DNA甲基化模式在某些临床疾病中可以被解释为“表观遗传回声”。
Kabuki syndrome (KS) is caused by mutations in KMT2D, which is a histone methyltransferase involved in methylation of H3K4, a histone marker associated with DNA methylation. Analysis of >450,000 CpGs in 24 KS patients with pathogenic mutations in KMT2D and 216 controls, identified 24 genomic regions, along with 1,504 CpG sites with significant DNA methylation changes including a number of Hox genes and the MYO1F gene. Using the most differentiating and significant probes and regions we developed a "methylation variant pathogenicity (MVP) score," which enables 100% sensitive and specific identification of individuals with KS, which was confirmed using multiple public and internal patient DNA methylation databases. We also demonstrated the ability of the MVP score to accurately reclassify variants of unknown significance in subjects with apparent clinical features of KS, enabling its potential use in molecular diagnostics. These findings provide novel insights into the molecular etiology of KS and illustrate that DNA methylation patterns can be interpreted as 'epigenetic echoes' in certain clinical disorders.