Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.

中文翻译：

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DNA甲基化表观特征对42例孟德尔神经发育障碍的诊断和表型相关性的评估。

遗传综合症经常表现出重叠的临床特征以及不确定的或不明确的遗传发现，这些发现可能会混淆准确的诊断和临床管理。已经显示出越来越多的遗传综合症具有独特的基因组DNA甲基化模式（称为“表位特征”）。外周血表象签名可用于诊断测试以及模棱两可的遗传测试结果的解释。我们在这里提出了一种在42种遗传综合征中进行表位映射的方法，该方法已经可以识别出34种健壮的疾病特异性表位。我们研究了新兴的重叠模式以及这些表位之间的相似性和层次关系，以突出它们的关键特征，因为它们与遗传异质性，剂量效应，未受影响的携带者状态，和不完整的外表。我们证明了进行准确遗传变异分类的多类建模的必要性，并展示了一次使用单个表位签名进行疾病分类有时会导致紧密相关的表位签名中的分类错误。我们通过大规模筛查发育迟缓和先天性异常的大批受试者，证明了该工具在解决模棱两可的临床病例和鉴定以前未被诊断的病例中的实用性。这项研究使已发表的具有DNA甲基化表位特征的综合症的数量增加了一倍以上，最重要的是，为受这些疾病影响的个体进行准确的诊断和临床评估开辟了新途径。我们证明了进行准确遗传变异分类的多类建模的必要性，并展示了一次使用单个表位签名进行疾病分类有时会导致紧密相关的表位签名中的分类错误。我们通过大规模筛查发育迟缓和先天性异常的大批受试者，证明了该工具在解决模棱两可的临床病例和鉴定以前未被诊断的病例中的实用性。这项研究使已发表的具有DNA甲基化表位特征的综合症的数量增加了一倍以上，最重要的是，为受这些疾病影响的个体进行准确的诊断和临床评估开辟了新途径。我们证明了进行准确遗传变异分类的多类建模的必要性，并展示了一次使用单个表位签名进行疾病分类有时会导致紧密相关的表位签名中的分类错误。我们通过大规模筛查发育迟缓和先天性异常的大批受试者，证明了该工具在解决模棱两可的临床病例和鉴定以前未被诊断的病例中的实用性。这项研究使已发表的具有DNA甲基化表位特征的综合症的数量增加了一倍以上，最重要的是，为受这些疾病影响的个体进行准确的诊断和临床评估开辟了新途径。