Precision Diagnostics for Vascular Malformations and Other Birth Defects

Mosaicism’s contribution to disease leads to new diagnostic tools

Technology Overview

Geneticist James Bennett, MD, PhD, studies “hidden” mutations — the genetic changes in our cells that were not inherited from our parents and are often present at very low frequencies in our bodies. Also known as genetic mosaicism or somatic mutations, these changes crop up after sperm meets egg and a single-celled embryo forms. Every cell division in our lifespans — all 10 quadrillion of them, on average — comes with a nonzero risk of a new mutation somewhere in the genome.

James BennettDr. James Bennett

Most of these mutations, known as somatic mutations, are harmless. But some of these variants can stealthily trigger disease. Tracking down disease-causing somatic mutations is difficult, because the population of cells with the mutation might exist in only one tissue or organ in the body and at low frequencies. Typical genetic sequencing techniques use DNA obtained from blood samples or a cheek swab and thus could miss these low-frequency mutations entirely.

Dr. Bennett has developed novel genetic sequencing methods with high sensitivity that can find these rare mutations in affected tissues that are removed during surgical procedures and biopsies. In 2023, he and collaborators from the University of Washington received a 5-year, $12.5 million grant from the National Institutes of Health as part of the SMaHT (Somatic Mosaicism across Human Tissues) Network, a collaborative initiative to trace somatic mutations in organs from 150 people to better understand the normal state of human genetic mosaicism.

Dr. Bennett, who is also a codirector of the Seattle Children’s Hospital Molecular Genetics Laboratory, has been studying the role of somatic mutations in vascular malformations, a type of birth defect that causes excess growth of blood or lymphatic vessels. In their most harmless and common state, vascular malformations in capillaries cause red or purple birthmarks, also known as port-wine stains. But if these malformations affect veins, arteries or the lymphatic system, overgrowth can impinge on neighboring tissues and cause difficulties with talking, swallowing or even breathing.

The typical treatment for vascular malformations is surgical removal of the overgrowth. Dr. Bennett and team, in collaboration with Seattle Children’s pediatric otolaryngologists Jonathan Perkins, DO, and Kaitlyn Zenner, MD, have studied somatic mosaicism in vascular malformations from tissues removed during surgery. They found that many patient cases are associated with somatic mutations in genes that are also common drivers of cancer. Several of these genes are targets of existing cancer drugs. Dr. Bennett and collaborators found that 80% of lymphatic malformations in children treated at Seattle Children’s were due to somatic mutations in the PIK3CA gene, which is a gene commonly mutated in solid tumors. Dr. Bennett has also identified somatic mutations associated with lymphatic malformations in the BRAF gene, which is also linked to cancer. Understanding the specific somatic mutations associated with malformations could lead to better precision treatments for these patients.

Dr. Bennett has also collaborated with Seattle Children’s pediatric otolaryngologist Juliana Bonilla-Velez, MD, and pediatric hematologist Whitney Eng, MD, on studies showing that existing cancer drugs (namely, Novartis’ alpelisib) that target PIK3CA can reduce the size and associated symptoms of vascular malformations in the head and neck. With these drugs, some of the patients were able to avoid more invasive surgeries that they would have otherwise needed.

Additionally, Dr. Bennett, in collaboration with Seattle Children’s pathologist Nya Nelson, MD, PhD, has developed a clinical sequencing panel called VANseq that tests for known somatic mutations in 46 genes that are associated with vascular malformations. The VANseq test is CLIA-certified (via the FDA Clinical Laboratory Improvement Amendments program) and is used to sequence patient samples both from the U.S. and internationally.

While tracking down somatic mutations is most reliable in the disease-affected tissues, Dr. Bennett has also led the development of new techniques to find these mutations in a patient’s blood. These techniques rely on a natural phenomenon known as cell-free DNA (cfDNA), in which all cells in our bodies shed DNA into our bloodstreams. By using sensitive genetic sequencing methods, Dr. Bennett has been able to identify rare somatic mutations using cfDNA.

He is also studying the potential roles of somatic mutations in other conditions, including other overgrowth disorders, epilepsy and craniofacial microsomia (a spectrum of abnormalities that affect development of the skull).

Currently available capabilities in the Bennett Lab include tissue, blood and cfDNA-based testing of somatic mutations. These techniques could be applied to testing for mutations associated with vascular malformations, a deeper understanding of genetic heterogeneity within clinical trial populations, and uncovering mutations associated with other rare diseases. Dr. Bennett has extensive expertise in highly sensitive genetic sequencing, cfDNA, exome sequencing, and other molecular genetics techniques.

Stage of Development

  • Preclinical in vitro
  • Clinical trials

Partnering Opportunities

  • Collaborative research and development
  • Sponsored research agreement
  • Consultation agreement
  • Data access

Publications

  1. Coorens THH, Oh JW, Choi YA … Bennett JT, et al. The Somatic Mosaicism across Human Tissues Network. Nature. 2025;643(8070):47-59.
  2. Zenner K, Jensen DM, Dmyterko V … Bennett JT. Somatic activating BRAF variants cause isolated lymphatic malformations. HGG Adv. 2022;3(2):100101.
  3. Wenger TL, Ganti S, Bull C … Bennett JT, et al. Alpelisib for the treatment of PIK3CA-related head and neck lymphatic malformations and overgrowth. Genet Med. 2022;24(11):2318-2328.
  4. Sheppard SE, Sanders VR, Srinivasan A … Bennett JT. Cerebrofacial vascular metameric syndrome is caused by somatic pathogenic variants in PIK3CA. Cold Spring Harb Mol Case Stud. 2021;7(6):a006147.
  5. Zenner K, Jensen DM, Cook TT … Bennett JT. Cell-free DNA as a diagnostic analyte for molecular diagnosis of vascular malformations. Genet Med. 2021;23(1):123-130.
  6. Zenner K, Cheng CV, Jensen DM … Bennett JT. Genotype correlates with clinical severity in PIK3CA-associated lymphatic malformations. JCI Insight. 2019;4(21):e129884.
  7. Luks VL, Kamitaki N, Vivero MP … Bennett JT, et al. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J Pediatr. 2015;166(4):1048-54.e1-5.

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Last updated May 13, 2026