Mirza-Schreiber Nazanin, Zech Michael, Wilson Rory, Brunet Theresa, Wagner Matias, Jech Robert, Boesch Sylvia, Škorvánek Matej, Necpál Ján, Weise David, Weber Sandrina, Mollenhauer Brit, Trenkwalder Claudia, Maier Esther M, Borggraefe Ingo, Vill Katharina, Hackenberg Annette, Pilshofer Veronika, Kotzaeridou Urania, Schwaibold Eva Maria Christina, Hoefele Julia, Waldenberger Melanie, Gieger Christian, Peters Annette, Meitinger Thomas, Schormair Barbara, Winkelmann Juliane, Oexle Konrad
Institute of Neurogenomics (ING), Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Neurogenetic Systems Analysis Group, Institute of Neurogenomics (ING), Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Brain. 2022 Apr 18;145(2):644-654. doi: 10.1093/brain/awab360.
Dystonia is a prevalent, heterogeneous movement disorder characterized by involuntarily abnormal postures. Biomarkers of dystonia are notoriously lacking. Here, a biomarker is reported for histone lysine methyltransferase (KMT2B)-deficient dystonia, a leading subtype among the individually rare monogenic dystonias. It was derived by applying a support vector machine to an episignature of 113 DNA CpG sites, which, in blood cells, showed significant epigenome-wide association with KMT2B deficiency and at least 1× log-fold change of methylation. This classifier was accurate both when tested on the general population and on samples with various other deficiencies of the epigenetic machinery, thus allowing for definitive evaluation of variants of uncertain significance and identifying patients who may profit from deep brain stimulation, a highly successful treatment in KMT2B-deficient dystonia. Methylation was increased in KMT2B deficiency at all 113 CpG sites. The coefficients of variation of the normalized methylation levels at these sites also perfectly classified the samples with KMT2B-deficient dystonia. Moreover, the mean of the normalized methylation levels correlated well with the age at onset of dystonia (P = 0.003)-being lower in samples with late or incomplete penetrance-thus serving as a predictor of disease onset and severity. Similarly, it may also function in monitoring the recently envisioned treatment of KMT2B deficiency by inhibition of DNA methylation.
肌张力障碍是一种常见的、异质性的运动障碍，其特征为不自主的异常姿势。肌张力障碍的生物标志物一直非常缺乏。在此，我们报告了一种组蛋白赖氨酸甲基转移酶（KMT2B）缺陷型肌张力障碍的生物标志物，KMT2B缺陷型肌张力障碍是单基因肌张力障碍中最主要的罕见亚型。该生物标志物是通过将支持向量机应用于113个DNA CpG位点的表观特征而得出的，这些位点在血细胞中显示出与KMT2B缺陷存在全表观基因组范围的显著关联，且甲基化至少有1×对数倍变化。当在普通人群以及具有各种其他表观遗传机制缺陷的样本上进行测试时，该分类器都很准确，因此能够对意义不确定的变异进行明确评估，并识别出可能从深部脑刺激中获益的患者，深部脑刺激是治疗KMT2B缺陷型肌张力障碍非常成功的方法。在KMT2B缺陷状态下，所有113个CpG位点的甲基化均增加。这些位点的标准化甲基化水平的变异系数也能完美地对KMT2B缺陷型肌张力障碍的样本进行分类。此外，标准化甲基化水平的平均值与肌张力障碍的发病年龄相关性良好（P = 0.003），在发病较晚或外显不完全的样本中该值较低，因此可作为疾病发病和严重程度的预测指标。同样，它也可能在监测最近设想的通过抑制DNA甲基化来治疗KMT2B缺陷方面发挥作用。
