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Abstract：
Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.
摘要：
临床表型的重叠和基因组关联的广度和复杂性的扩大是孟德尔疾病的诊断和临床管理中日益严峻的挑战。基因组变异的功能后果和临床影响可能涉及独特的，特定疾病，基因组DNA甲基化表观标记。在这项研究中,我们描述了19种新的表观特征疾病,并将这些发现与38种以前建立的表观特征进行了比较,得出与65种遗传综合征相关的57种表观特征.我们证明了增加的分辨率和特异性，从蛋白质复合物，基因，亚基因，蛋白质结构域，甚至是单核苷酸水平的孟德尔表标记。我们展示了多类建模开发高度准确和疾病特异性诊断分类器的能力。这项研究极大地扩展了具有可检测的DNA甲基化表观特征的疾病的数量和范围，通过解决未解决的病例和临床意义未知的变异的重新分类，提高临床诊断能力，并提供了对孟德尔疾病的分子病因的进一步了解。
