Scholarlink

<p>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<sup>TM</sup> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Clinical utility of DNA-methylation signatures in routine diagnostics for neurodevelopmental disorders

  • 期刊论文

  • 发表日期：

    2025年7月29日

查看全文
  • Daphne J. Smits,
  • Christophe Debuy,
  • Alice S. Brooks,
  • Rachel Schot,
  • Federico Ferraro,
  • Dmitrijs Rots,
  • Arjan Bouman,
  • Virginie J. M. Verhoeven,
  • Laura Donker Kaat,
  • Sarina G. Kant,
  • Yolande van Bever,
  • Serwet Demirdas,
  • Shimriet Zeidler,
  • Marieke F. van Dooren,
  • Stephany H. Donze,
  • Lies H. Hoefsloot,
  • Marjon A. van Slegtenhorst,
  • Martina Wilke,
  • Frank Sleutels,
  • Mark Drost,
  • Hennie T. Brüggenwirth,
  • Rick van Minkelen,
  • Anne Goverde,
  • Janna A. Hol,
  • Ingrid M. B. H. van de Laar,
  • Yvette van Ierland,
  • Anneke Kievit,
  • Vyne van der Schoot,
  • Kyra E. Stuurman,
  • Grazia M. S. Mancini,
  • Marja W. Wessels,
  • Tjakko J. van Ham,
  • Tjitske Kleefstra,
  • Tahsin Stefan Barakat

摘要

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 EpisignTM 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.