Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, Canada.
Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
Genet Med. 2024 May;26(5):101075. doi: 10.1016/j.gim.2024.101075. Epub 2024 Jan 18.
This study aims to assess the diagnostic utility and provide reporting recommendations for clinical DNA methylation episignature testing based on the cohort of patients tested through the EpiSign Clinical Testing Network.
The EpiSign assay utilized unsupervised clustering techniques and a support vector machine-based classification algorithm to compare each patient's genome-wide DNA methylation profile with the EpiSign Knowledge Database, yielding the result that was reported. An international working group, representing distinct EpiSign Clinical Testing Network health jurisdictions, collaborated to establish recommendations for interpretation and reporting of episignature testing.
Among 2399 cases analyzed, 1667 cases underwent a comprehensive screen of validated episignatures, imprinting, and promoter regions, resulting in 18.7% (312/1667) positive reports. The remaining 732 referrals underwent targeted episignature analysis for assessment of sequence or copy-number variants (CNVs) of uncertain significance or for assessment of clinical diagnoses without confirmed molecular findings, and 32.4% (237/732) were positive. Cases with detailed clinical information were highlighted to describe various utility scenarios for episignature testing.
Clinical DNA methylation testing including episignatures, imprinting, and promoter analysis provided by an integrated network of clinical laboratories enables test standardization and demonstrates significant diagnostic yield and clinical utility beyond DNA sequence analysis in rare diseases.
本研究旨在评估基于通过 EpiSign 临床检测网络检测的患者队列的临床 DNA 甲基化表观遗传标志物检测的诊断效用，并提供报告建议。
EpiSign 检测采用无监督聚类技术和基于支持向量机的分类算法，将每位患者的全基因组 DNA 甲基化图谱与 EpiSign 知识数据库进行比较，得出报告结果。一个代表不同 EpiSign 临床检测网络健康管辖区的国际工作组合作，为表观遗传标志物检测的解释和报告制定建议。
在分析的 2399 例病例中，1667 例进行了全面的验证表观遗传标志物、印迹和启动子区域筛选，阳性报告率为 18.7%（312/1667）。其余 732 例转介进行靶向表观遗传标志物分析，以评估不确定意义的序列或拷贝数变异（CNVs）或评估无明确分子发现的临床诊断，阳性率为 32.4%（237/732）。对有详细临床信息的病例进行了重点描述，以描述表观遗传标志物检测的各种实用场景。
包括印迹和启动子分析在内的临床 DNA 甲基化检测，由临床实验室的综合网络提供，可实现检测标准化，并在罕见疾病中展示了除 DNA 序列分析之外具有显著诊断收益和临床效用的检测。
