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Abstract：
Analysis of genomic DNA methylation by generating epigenetic signature profiles (episignatures) is increasingly being implemented in genetic diagnosis. Here we report our experience using episignature analysis to resolve both uncomplicated and complex cases of neurodevelopmental disorders (NDDs). We analyzed 97 NDDs divided into (1) a validation cohort of 59 patients with likely pathogenic/pathogenic variants characterized by a known episignature and (2) a test cohort of 38 patients harboring variants of unknown significance or unidentified variants. The expected episignature was obtained in most cases with likely pathogenic/pathogenic variants (53/59 [90%]), a revealing exception being the overlapping profile of two SMARCB1 pathogenic variants with ARID1A/B:c.6200, confirmed by the overlapping clinical features. In the test cohort, five cases showed the expected episignature, including (1) novel pathogenic variants in ARID1B and BRWD3; (2) a deletion in ATRX causing MRXFH1 X-linked mental retardation; and (3) confirmed the clinical diagnosis of Cornelia de Lange (CdL) syndrome in mutation-negative CdL patients. Episignatures analysis of the in BAF complex components revealed novel functional protein interactions and common episignatures affecting homologous residues in highly conserved paralogous proteins (SMARCA2 M856V and SMARCA4 M866V). Finally, we also found sex-dependent episignatures in X-linked disorders. Implementation of episignature profiling is still in its early days, but with increasing utilization comes increasing awareness of the capacity of this methodology to help resolve the complex challenges of genetic diagnoses.
摘要：
通过产生表观遗传特征谱（“表观特征”）分析基因组DNA甲基化越来越多地在遗传诊断中实现。在这里，我们报告了我们使用表观特征分析来解决神经发育障碍（NDD）的简单和复杂病例的经验。我们分析了97个NDD，分为：（i）59例具有已知表观特征的可能致病性/致病性变异的患者的验证队列，以及（ii）38例具有未知显着性变异（VUS）或未识别变异的患者的测试队列。在大多数具有可能的致病性/致病性变异的病例中获得了预期的表观特征(53/59;90%),一个明显的例外是两个SMARCB1致病性变异体与ARID1A/B的重叠特征：c.6200，由重叠的临床特征证实。在测试队列中，5例显示了预期的表观特征，包括：（i）ARID1B和BRWD3的新型致病变异；（ii）ATRX缺失导致MRXFH1X相关智力低下，以及（iii）在突变阴性的CdL患者中证实了CorneliadeLange（CdL）综合征的临床诊断。BAF复合物成分的表观特征分析揭示了新的功能性蛋白质相互作用和影响高度保守的旁系蛋白质（SMARCA2M856V和SMARCA4M866V）中同源残基的常见表观标记。最后,我们还在X连锁疾病中发现了性别依赖的表观特征.表特征谱分析的实施仍处于早期阶段，但随着越来越多的利用，人们越来越意识到这种方法的能力，以帮助解决遗传诊断的复杂挑战。
