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Published on: October 11, 2021
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High depth targeted next-generation sequencing in vascular malformations.
Pattima Pakhathirathien1,2, Parith Wongkittichote1, Sanchawan Wittayakornrerk3
1Division of Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Ratchatewi, Bangkok 10400, Thailand.
Human Molecular Genetics
|November 12, 2025
Summary
Genetic testing identified causative mutations in 80.8% of vascular malformation patients. PIK3CA and TEK gene mutations were most common, suggesting targeted therapies may benefit patients.
Area of Science:
- Vascular biology and genetics
- Medical genomics
- Oncology
Background:
- Vascular anomalies encompass tumors and malformations, with malformations classified as fast-flow (e.g., arteriovenous malformation) or slow-flow (e.g., venous malformation).
- Somatic mutations in signaling pathways like PIK3/AKT/mTOR and RAS/MAPK/ERK are increasingly recognized as key drivers of vascular malformations.
- Accurate genetic diagnosis is crucial for understanding disease mechanisms and developing targeted treatments.
Purpose of the Study:
- To investigate the genetic underpinnings of various vascular malformations using high-depth next-generation sequencing (NGS).
- To determine the diagnostic yield of a comprehensive gene panel test for identifying causative somatic mutations.
- To explore the potential for targeted therapeutic interventions based on identified genetic variants.
Main Methods:
- Conducted gene panel testing (129 genes) with high-depth NGS on tissue samples from 26 patients with mixed vascular malformations (2 fast-flow, 24 slow-flow).
- Analyzed sequencing data to detect low-level mosaic variants (down to ~1%) associated with vascular anomalies.
- Identified and characterized pathogenic/likely pathogenic (P/LP) variants, including novel mutations.
Main Results:
- Achieved an 80.8% diagnostic rate, identifying P/LP variants in 21 out of 26 patients.
- PIK3CA (57.1%) and TEK (33.3%) were the most frequently mutated genes, particularly in slow-flow malformations.
- HRAS and GNAQ mutations were found in fast-flow malformations, and three novel P/LP variants were discovered.
Conclusions:
- High-depth NGS gene panel testing is highly effective for diagnosing vascular malformations, with an 80.8% diagnostic yield.
- Somatic mutations in PIK3CA and TEK are prevalent in slow-flow vascular malformations, highlighting their significance.
- Findings support the potential efficacy of targeted therapies, such as mTOR inhibitors, for patients with specific genetic mutations in vascular anomalies.
