Recent studies have shown that the PI3K signaling pathway plays an important role in the pathogenesis of slow-flow vascular malformations (SFVMs). Analysis of genetic mutations has advanced our understanding of the mechanisms involved in SFVM pathogenesis and may identify new therapeutic targets. We screened for somatic variants in a cohort of patients with SFVMs using targeted next-generation sequencing. Targeted next-generation sequencing of 29 candidate genes associated with vascular anomalies or with the PI3K signaling pathway was performed on affected tissues from patients with SFVMs. Fifty-nine patients with SFVMs (venous malformations n = 21, lymphatic malformations n = 27, lymphatic venous malformations n = 1, and Klippel–Trenaunay syndrome n = 10) were included in the study. TEK and PIK3CA were the most commonly mutated genes in the study. We detected eight TEK pathogenic variants in 10 samples (16.9%) and three PIK3CA pathogenic variants in 28 samples (47.5%). In total, 37 of 59 patients (62.7%) with SFVMs harbored pathogenic variants in these three genes involved in the PI3K signaling pathway. Inhibitors of this pathway may prove useful as molecular targeted therapies for SFVMs.
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We are grateful to the patients and their families for their invaluable contributions to this study. We thank Drs. Shiho Yasue, Saori Endo, and Mariko Seishima of Gifu University for their assistance with data analysis. We thank Dr. Koki Nagai of Tohoku University for providing technical assistance with TA cloning analysis. We also thank the Department of Pediatrics at Gifu University for their contribution. We thank Dr. Laurence M. Boon of Saint Luc University Hospital, Dr. Miikka Vikkula of University of Louvain, and Dr. Hiroshi Nagabukuro and Dr. Akira Tanaka of ARTham Therapeutics for helpful discussions and suggestions. We also thank Yuichi Arakawa and Kuniko Kikuchi of Axcelead Drug Discovery Partners, Inc., for technical assistance, and Anne M. O’Rourke, PhD, from Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.
This study was supported in part by a Clinical Research-Clinical Trial Promotion Research Project grant (19lk0201089h0001) from the Japan Agency for Medical Research and Development and by funding from ARTham Therapeutics, Inc.
Some of the authors declared Financial and Non-Financial Relationships and Activities, and Conflicts of Interest regarding this manuscript as indicated in the supplementary materials.
This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines and approved by the ethics committee or institutional review board of each institution.
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Nozawa, A., Fujino, A., Yuzuriha, S. et al. Comprehensive targeted next-generation sequencing in patients with slow-flow vascular malformations. J Hum Genet 67, 721–728 (2022). https://doi.org/10.1038/s10038-022-01081-6