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Background <p>Schwannomatosis (SWN) is a rare tumor predisposition syndrome caused by pathogenic variants in <i>NF2</i>, <i>SMARCB1</i>, or <i>LZTR1</i>. Mosaicism contributes to up to 30% of de novo<i> NF2-</i>related cases, but its role in <i>SMARCB1</i>- and <i>LZTR1</i>-related SWN remains unclear. Accurate molecular classification is critical for clinical management, yet overlapping phenotypes complicate diagnosis. Because standard diagnostics have limited sensitivity and often require tumor tissue, we evaluated whether ultra-sensitive duplex sequencing of blood-derived DNA improves mosaic variant detection in SWN.</p> Methods <p>We developed a duplex sequencing assay targeting <i>NF2, SMARCB1,</i> and <i>LZTR1</i> and analyzed 102 individuals with suspected SWN previously negative for constitutional pathogenic variants, along with 35 controls.</p> Results <p>Duplex sequencing identified low-level mosaic <i>NF2</i> pathogenic variants in 11% of cases (11/102), with variant allele frequencies as low as 0.06%. In all patients with available tumor material (8/11), blood and tumor findings were concordant. No mosaic pathogenic variants were detected in <i>SMARCB1</i> or <i>LZTR1</i>. Controls showed no deleterious variants except one <i>LZTR1</i> splice-site variant.</p> Conclusions <p>Duplex sequencing enables robust detection of ultra-low-frequency <i>NF2</i> variants in SWN and complements existing diagnostic workflows. This approach may reduce dependence on tumor tissue in <i>NF2</i>-related SWN, improve differential diagnosis, and support patient management and genetic counseling.</p>

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From clinical suspicion to molecular detection of low-level mosaicism in NF2-related schwannomatosis via ultra-sensitive duplex sequencing

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • Monika Horbacz,
  • Justyna Prokopiuk,
  • Elisabeth Castellanos,
  • Hilde Brems,
  • Ignacio Blanco,
  • Eric Legius,
  • Seppe Van der Auweraer,
  • Shehab Moukbel Ali Aldawla,
  • Atena Yasari,
  • Monika Heinzl,
  • Piotr Madanecki,
  • Natalia Filipowicz,
  • Aleksandra Gintowt-Chakour,
  • Beata S. Lipska-Ziętkiewicz,
  • Jan P. Dumanski,
  • Irene Tiemann-Boege,
  • Arkadiusz Piotrowski,
  • Magdalena Koczkowska

摘要

Background

Schwannomatosis (SWN) is a rare tumor predisposition syndrome caused by pathogenic variants in NF2, SMARCB1, or LZTR1. Mosaicism contributes to up to 30% of de novo NF2-related cases, but its role in SMARCB1- and LZTR1-related SWN remains unclear. Accurate molecular classification is critical for clinical management, yet overlapping phenotypes complicate diagnosis. Because standard diagnostics have limited sensitivity and often require tumor tissue, we evaluated whether ultra-sensitive duplex sequencing of blood-derived DNA improves mosaic variant detection in SWN.

Methods

We developed a duplex sequencing assay targeting NF2, SMARCB1, and LZTR1 and analyzed 102 individuals with suspected SWN previously negative for constitutional pathogenic variants, along with 35 controls.

Results

Duplex sequencing identified low-level mosaic NF2 pathogenic variants in 11% of cases (11/102), with variant allele frequencies as low as 0.06%. In all patients with available tumor material (8/11), blood and tumor findings were concordant. No mosaic pathogenic variants were detected in SMARCB1 or LZTR1. Controls showed no deleterious variants except one LZTR1 splice-site variant.

Conclusions

Duplex sequencing enables robust detection of ultra-low-frequency NF2 variants in SWN and complements existing diagnostic workflows. This approach may reduce dependence on tumor tissue in NF2-related SWN, improve differential diagnosis, and support patient management and genetic counseling.