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<p>Rett syndrome (RTT) is a severe neurodevelopmental disorder, with <i>MECP2</i> mutations accounting for 90–95% of classic and 50–70% of atypical cases. However, many clinically diagnosed RTT patients remain without molecular diagnoses. While point mutations and large rearrangements in <i>MECP2</i> are well studied, the role of small-intermediate structural variants (SVs) remains mostly elusive. Using standard short-read whole genome sequencing, we identified novel de novo SVs in three out of three previously unresolved RTT cases: a complex SV with two deletions ( ~ 5Kbp and ~60Kbp) and a ~105Kbp inversion; a ~200Kbp translocation; and a ~3Kbp deletion. These findings suggest that such elusive SVs might be a common cause for “<i>MECP2</i>-negative” RTT. Incorporating SV detection into routine genetic testing through bioinformatic analysis of short-read sequencing or manual review using IGV could improve diagnostic rates and expand our understanding of RTT and similar disorders.</p>

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Unraveling MECP2 structural variants in previously elusive Rett syndrome cases through IGV interpretation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月13日

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  • Tomer Poleg,
  • Noam Hadar,
  • Gali Heimer,
  • Vadim Dolgin,
  • Ilana Aminov,
  • Amit Safran,
  • Nadav Agam,
  • Matan M. Jean,
  • Ofek Freund,
  • Simran Kaur,
  • John Christodoulou,
  • Bruria Ben-Zeev,
  • Ohad S. Birk

摘要

Rett syndrome (RTT) is a severe neurodevelopmental disorder, with MECP2 mutations accounting for 90–95% of classic and 50–70% of atypical cases. However, many clinically diagnosed RTT patients remain without molecular diagnoses. While point mutations and large rearrangements in MECP2 are well studied, the role of small-intermediate structural variants (SVs) remains mostly elusive. Using standard short-read whole genome sequencing, we identified novel de novo SVs in three out of three previously unresolved RTT cases: a complex SV with two deletions ( ~ 5Kbp and ~60Kbp) and a ~105Kbp inversion; a ~200Kbp translocation; and a ~3Kbp deletion. These findings suggest that such elusive SVs might be a common cause for “MECP2-negative” RTT. Incorporating SV detection into routine genetic testing through bioinformatic analysis of short-read sequencing or manual review using IGV could improve diagnostic rates and expand our understanding of RTT and similar disorders.