Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, Ontario, Canada.
J Mol Diagn. 2017 Nov;19(6):848-856. doi: 10.1016/j.jmoldx.2017.07.002. Epub 2017 Aug 12.
Genomic imprinting involves a DNA methylation-dependent and parent-of-origin-specific regulation of gene expression. Clinical assays for imprinting disorders are genomic locus, disorder, and molecular defect specific. We aimed to clinically validate a genome-wide approach for simultaneous testing of common imprinting disorders in a single assay. Using genome-wide DNA methylation arrays, epigenetic profiles from peripheral blood of patients with Angelman, Prader-Willi, Beckwith-Wiedemann, or Silver-Russell syndromes were compared to a reference cohort of 361 unaffected individuals. The analysis was of developmental delay and intellectual disabilities. This approach has allowed 100% sensitivity and specificity in detecting imprinting defects in all 28 patients and enabled identification of defects beyond the classically tested imprinted loci. Analysis of the cohort of patients with developmental delay and intellectual disabilities identified two patients with Prader-Willi syndrome, one with Beckwith-Wiedemann syndrome, and several other patients with DNA methylation defects in novel putative imprinting loci. These findings demonstrate clinical validation of a sensitive and specific genome-wide DNA methylation array-based approach for molecular testing of imprinting disorders to allow simultaneous assessment of genome-wide epigenetic defects in a single analytical procedure, enabling replacement of multiple locus-specific molecular tests while allowing discovery of novel clinical epigenomic associations and differential diagnosis of other epigenomic disorders.
基因组印记涉及 DNA 甲基化依赖性和亲本来源特异性的基因表达调控。针对印记障碍的临床检测是针对基因组位置、障碍和分子缺陷特异性的。我们旨在通过一种全基因组方法，在单次检测中同时测试常见的印记障碍，从而对其进行临床验证。使用全基因组 DNA 甲基化阵列，我们比较了患有 Angelman、Prader-Willi、Beckwith-Wiedemann 或 Silver-Russell 综合征患者外周血的表观遗传谱与 361 名未受影响个体的参考队列。该分析针对的是发育迟缓伴智力障碍。这种方法在所有 28 名患者中实现了 100%的敏感性和特异性，能够检测到经典测试印迹基因座以外的缺陷。对发育迟缓伴智力障碍患者队列的分析确定了两名 Prader-Willi 综合征患者、一名 Beckwith-Wiedemann 综合征患者，以及其他几名在新的推定印记基因座中存在 DNA 甲基化缺陷的患者。这些发现证明了一种敏感和特异性的全基因组 DNA 甲基化阵列为基础的方法在分子检测印记障碍方面的临床验证，该方法允许在单个分析过程中同时评估全基因组的表观遗传缺陷，替代多个基因座特异性分子检测，同时允许发现新的临床表观基因组关联，并对其他表观基因组障碍进行鉴别诊断。
