Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders
Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders
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DOI：
10.1016/j.ajhg.2020.01.019
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发表时间：
2020-03-05
影响因子：
9.8
通讯作者：
Sadikovic, Bekim
中科院分区：
文献类型：
--
作者：
Aref-Eshghi, Erfan;Kerkhof, Jennifer;Sadikovic, Bekim
遗传综合征经常出现重叠的临床特征和不确定或模糊的遗传学发现，这可能会混淆准确的诊断和临床治疗。越来越多的遗传综合征已被证明具有独特的基因组DNA甲基化模式（称为"表观特征"）。外周血episignatures可用于诊断测试以及用于解释不明确的基因测试结果。我们在这里提出了一种方法，episignature映射在42个遗传综合征，这使得34个强大的疾病特异性episignatures的识别。我们研究了重叠的新模式，以及这些episignatures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全遗传有关。我们证明了准确的遗传变异分类的多类建模的必要性，并展示了如何使用一个单一的episignature在一个时间疾病分类有时会导致分类错误密切相关的episignature。我们证明了这种工具在解决模棱两可的临床病例和识别以前未确诊的情况下，通过大规模筛查一个大队列的受试者发育迟缓和先天性异常的效用。这项研究使已发表的具有DNA甲基化表观特征的综合征数量增加了一倍多，最重要的是，为受这些疾病影响的个体的准确诊断和临床评估开辟了新的途径。
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.