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Background <p>This study aimed to assess the detection rate and spectrum of pathogenic variants (PVs) and candidate variants (variants of uncertain significance, VUS) in AVM patients.</p> Methods <p>In this retrospective multicenter cohort study, tissue and blood samples were collected from 114 patients with extracranial AVMs during treatment or when clinically indicated, for dedicated molecular genetic analyses. PVs (solved) and VUS were detected by targeted sequencing on DNA using gene panels analyzing genes suspected to be associated with AVMs. Unsolved cases were further categorized into unrestricted and restricted, with the latter reflecting methodological limitations. Subgroup analyses were carried out based on affected genes to explore associated genotype–phenotype correlations.</p> Results <p>PVs were identified in 80.7% (92/114) and VUS in 5.3% (6/114), resulting in a total detection rate of 86.0% (98/114). Unsolved cases accounted for 11.4% (13/114) including 6/13 (46.2%) with methodological restrictions. Somatic PVs were most frequent in KRAS (21.1%, 24/114), <i>MAP2K1</i> (17.5%, 20/114), <i>HRAS</i> (8.8%, 10/114), and <i>BRAF</i> (7.9%, 9/114). Germline variants were found in <i>RASA1</i> (7.0%, 8/114), <i>PTEN</i> (5.3%, 6/114), and <i>EPHB4</i> (3.5%, 4/114). In a few cases, somatic variants in <i>RASA1</i> (1.8%, 2/114) and <i>PTEN</i> (2.6%, 3/114) were identified. Additional PVs occurred in <i>PIK3CA</i> (3.5%, 4/114), <i>SOS1</i> (2.6%, 3/114), <i>GNAQ</i> (1.8%, 2/114), and <i>RIT1, RAF1</i>, and <i>GNA14</i> (each 0.9%, 1/114). Within the RAS/MAPK pathway, <i>RAS</i> variants (<i>KRAS</i>, <i>HRAS</i>) were linked to more severe clinical stages (65.6% vs. 40.0% <i>MAP2K1 and 37.5</i>% <i>BRAF</i>, <i>p</i> = 0.027) and higher relapse rates (55.6% vs. 43.8% <i>MAP2K1 and 0</i>% <i>BRAF</i>, <i>p</i> = 0.049). Germline variants showed a distinct distribution pattern with more syndromic presentations (61.1% vs. 15.6%, <i>p</i> &lt; 0.001) compared to mosaic variants.</p> Conclusions <p>Broad and sensitive testing enables a high detection rate of causative variants in AVMs. PVs and VUS detected reveal a broader genetic spectrum than previously recognized. Somatic <i>RAS</i> PVs were associated with more advanced disease stages and higher relapse rates than <i>MAP2K1</i> and <i>BRAF</i> variants, while germline variants were more frequently linked to syndromic patterns.</p>

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Detection rate and mutational landscape in extracranial arteriovenous malformations: a cohort study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月16日

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  • Vanessa F. Schmidt,
  • Denny Schanze,
  • Richard Brill,
  • Julius H. Loeser,
  • Wibke Uller,
  • Michael Doppler,
  • Özlem Cangir,
  • Susanne Hengst,
  • Veronika Vielsmeier,
  • Maciej Pech,
  • Florian Obereisenbuchner,
  • Mirjam Schirren,
  • Alena Sint,
  • Daniel Puhr-Westerheide,
  • Sinan Deniz,
  • Jakob B. W. Weiß,
  • Beate Häberle,
  • Alexandra Hartel,
  • Alexandra Fröba-Pohl,
  • Julia Haehl,
  • Annegret Holm,
  • Peter B. Sporns,
  • Thomas Scherf,
  • Jens Ricke,
  • Silke Lassmann,
  • Max Seidensticker,
  • Walter A. Wohlgemuth,
  • Melanie A. Kimm,
  • Martin Zenker,
  • Moritz Wildgruber,
  • Friedrich G. Kapp

摘要

Background

This study aimed to assess the detection rate and spectrum of pathogenic variants (PVs) and candidate variants (variants of uncertain significance, VUS) in AVM patients.

Methods

In this retrospective multicenter cohort study, tissue and blood samples were collected from 114 patients with extracranial AVMs during treatment or when clinically indicated, for dedicated molecular genetic analyses. PVs (solved) and VUS were detected by targeted sequencing on DNA using gene panels analyzing genes suspected to be associated with AVMs. Unsolved cases were further categorized into unrestricted and restricted, with the latter reflecting methodological limitations. Subgroup analyses were carried out based on affected genes to explore associated genotype–phenotype correlations.

Results

PVs were identified in 80.7% (92/114) and VUS in 5.3% (6/114), resulting in a total detection rate of 86.0% (98/114). Unsolved cases accounted for 11.4% (13/114) including 6/13 (46.2%) with methodological restrictions. Somatic PVs were most frequent in KRAS (21.1%, 24/114), MAP2K1 (17.5%, 20/114), HRAS (8.8%, 10/114), and BRAF (7.9%, 9/114). Germline variants were found in RASA1 (7.0%, 8/114), PTEN (5.3%, 6/114), and EPHB4 (3.5%, 4/114). In a few cases, somatic variants in RASA1 (1.8%, 2/114) and PTEN (2.6%, 3/114) were identified. Additional PVs occurred in PIK3CA (3.5%, 4/114), SOS1 (2.6%, 3/114), GNAQ (1.8%, 2/114), and RIT1, RAF1, and GNA14 (each 0.9%, 1/114). Within the RAS/MAPK pathway, RAS variants (KRAS, HRAS) were linked to more severe clinical stages (65.6% vs. 40.0% MAP2K1 and 37.5% BRAF, p = 0.027) and higher relapse rates (55.6% vs. 43.8% MAP2K1 and 0% BRAF, p = 0.049). Germline variants showed a distinct distribution pattern with more syndromic presentations (61.1% vs. 15.6%, p < 0.001) compared to mosaic variants.

Conclusions

Broad and sensitive testing enables a high detection rate of causative variants in AVMs. PVs and VUS detected reveal a broader genetic spectrum than previously recognized. Somatic RAS PVs were associated with more advanced disease stages and higher relapse rates than MAP2K1 and BRAF variants, while germline variants were more frequently linked to syndromic patterns.