Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations

Kaitlyn Zenner, Dana M. Jensen, Tori T. Cook, Victoria Dmyterko, Randall A. Bly, Sheila Ganti, Ghayda M. Mirzaa, William B. Dobyns, Jonathan A. Perkins, James T. Bennett

Research output: Contribution to journalArticle


Purpose: Vascular malformations (VM) are primarily caused by somatic activating pathogenic variants in oncogenes. Targeted pharmacotherapies are emerging but require molecular diagnosis. Since variants are currently only detected in malformation tissue, patients may be ineligible for clinical trials prior to surgery. We hypothesized that cell-free DNA (cfDNA) could provide molecular diagnoses for patients with isolated VM. Methods: cfDNA was isolated from plasma or cyst fluid from patients with arteriovenous malformations (AVM), venous malformations (VeM), or lymphatic malformations (LM), and assayed for known pathogenic variants using droplet digital polymerase chain reaction (ddPCR). Cyst fluid cfDNA from an independent cohort of LM patients was prospectively screened for variants using a multiplex ddPCR assay. Results: Variants were detected in plasma cfDNA in patients with AVM (2/8) and VeM (1/3). Variants were detected in cyst fluid cfDNA (7/7) but not plasma (0/26) in LM patients. Prospective testing of cyst fluid cfDNA with multiplex ddPCR identified variants in LM patients who had never undergone surgery (4/5). Conclusion: Variants were detected in plasma from AVM and VeM patients, and in cyst fluid from patients with LM. These data support investigation of cfDNA-based molecular diagnostics for VM patients, which may provide opportunities to initiate targeted pharmacotherapies without prior surgery.

Original languageEnglish (US)
JournalGenetics in Medicine
StateAccepted/In press - 2020
Externally publishedYes


  • cell-free DNA
  • droplet digital PCR
  • multiplexing
  • PIK3CA
  • vascular malformations

PubMed: MeSH publication types

  • Journal Article

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