Smits Daphne J, Debuy Christophe, Brooks Alice S, Schot Rachel, Ferraro Federico, Rots Dmitrijs, Bouman Arjan, Verhoeven Virginie J M, Donker Kaat Laura, Kant Sarina G, van Bever Yolande, Demirdas Serwet, Zeidler Shimriet, van Dooren Marieke F, Donze Stephany H, Hoefsloot Lies H, van Slegtenhorst Marjon A, Wilke Martina, Sleutels Frank, Drost Mark, Brüggenwirth Hennie T, van Minkelen Rick, Goverde Anne, Hol Janna A, van de Laar Ingrid M B H, van Ierland Yvette, Kievit Anneke, van der Schoot Vyne, Stuurman Kyra E, Mancini Grazia M S, Wessels Marja W, van Ham Tjakko J, Kleefstra Tjitske, Barakat Tahsin Stefan
Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
Genetics Laboratory, Children's Clinical University Hospital, Riga, Latvia.
Eur J Hum Genet. 2025 Jul 29. doi: 10.1038/s41431-025-01919-5.
Disease-causing variants in chromatin regulator genes cause many developmental disorders. DNA methylation (DNAm) signatures are emerging as a diagnostic tool to identify disease causes and classify variants of uncertain significance (VUS). This study evaluates their diagnostic utility in a routine clinical setting. We retrospectively analyzed 298 patients from the Erasmus MC who underwent DNAm signature testing using the commercial Episign platform between February 2019 and June 2023. The cohort included 75 targeted analyses for follow-up on prior genetic findings and 223 complete analyses for cases unsolved after prior diagnostic testing. In the 75 targeted analyses, DNAm signatures were positive in 18% (10/55) for (VUS), 91% (10/11) for likely pathogenic variants, and 89% (8/9) for pathogenic variants. In 223 complete analyses, a disease-linked DNAm signature was observed in 9.0% (20/223), with a (partial) phenotypic match in 55% of those (11/20) but no match in 45% (9/20). In 81.8% (9/11) of those DNAm signature positive cases with a phenotypic match, retrospective analysis identified a causative DNA variant or confirmed independently an imprinting disorder that was unidentified previously, providing valuable diagnostic insights with an overall diagnostic yield of 4.0% (9/223) for these molecular confirmed cases. In conclusion, this study supports the clinical utility of DNAm signatures to assist in interpreting and classifying VUS, but also as a complementary tool when prior genetic testing, including exome sequencing, failed to provide a diagnosis.
染色质调节基因中的致病变异会导致许多发育障碍。DNA甲基化（DNAm）特征正逐渐成为一种诊断工具，用于确定疾病病因并对意义未明的变异（VUS）进行分类。本研究评估了它们在常规临床环境中的诊断效用。我们回顾性分析了298例来自伊拉斯姆斯医学中心的患者，这些患者在2019年2月至2023年6月期间使用商业Episign平台进行了DNAm特征检测。该队列包括75项针对先前遗传发现的后续靶向分析，以及223项针对先前诊断检测后仍未解决的病例的完整分析。在75项靶向分析中，DNAm特征对于VUS呈阳性的比例为18%（10/55），对于可能的致病变异为91%（10/11），对于致病变异为89%（8/9）。在223项完整分析中，观察到9.0%（20/223）存在与疾病相关的DNAm特征，其中55%（11/20）有（部分）表型匹配，但45%（9/20）无匹配。在那些DNAm特征呈阳性且有表型匹配的病例中，81.8%（9/11）的回顾性分析确定了致病DNA变异，或独立证实了先前未识别的印记障碍，这些分子确诊病例的总体诊断率为4.0%（9/223），提供了有价值的诊断见解。总之，本研究支持DNAm特征在协助解释和分类VUS方面的临床效用，同时也支持其作为先前包括外显子组测序在内的基因检测未能提供诊断时的补充工具。
