High depth targeted next-generation sequencing in vascular malformations
Issued Date
2026-02-08
Resource Type
eISSN
14602083
Scopus ID
2-s2.0-105029628439
Pubmed ID
41224725
Journal Title
Human Molecular Genetics
Volume
35
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Human Molecular Genetics Vol.35 No.1 (2026)
Suggested Citation
Pakhathirathien P., Wongkittichote P., Wittayakornrerk S., Treesit T., Feinggumloon S., Pichipichatkul K., Bua-Ngam C., Sarovath A., Thanachatchairattana P., Dumrongwongsiri S., Bowling K.M., Corliss M.M., Cao Y., Tim-Aroon T., Khongkraparn A., Noojaroen S., Wattanasirichaigoon D. High depth targeted next-generation sequencing in vascular malformations. Human Molecular Genetics Vol.35 No.1 (2026). doi:10.1093/hmg/ddaf169 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/115083
Title
High depth targeted next-generation sequencing in vascular malformations
Corresponding Author(s)
Other Contributor(s)
Abstract
A vascular anomaly could be a vascular tumor or a vascular malformation. Vascular malformation is subclassified into fast-flow, including arteriovenous malformation and portwine stain, and slow-flow group comprising venous malformation, lymphatic malformation, and venolymphatic malformation. Recent data have shown that somatic mutations of genes in PIK3/AKT/mTOR and RAS/MAPK/ERK pathways are a major cause of this disorder. We conducted a gene panel testing (129 genes) with high-depth next-generation sequencing (NGS), which can detect very low-level mosaicism (~ 1%), on the tissue obtained from 26 patients in a cohort of mixed types of vascular malformation, comprising 2 fast-flow and 24 slow-flow malformations. Pathogenic/likely pathogenic (P/LP) variants were identified in 21 of 26 patients, yielding the overall diagnostic rate of 80.8%. The leading causes identified were PIK3CA (57.1%) and TEK (33.3%), especially in the slow-flow group, whereas HRAS and GNAQ were found positive in patients with fast-flow malformations. Three of 11 P/LP variants were previously unreported in vascular malformation, including those from HRAS, PIK3CA, and TEK. Most variants were detected as a solo, except for double mutations of TEK in patients with blue rubber bleb nevus syndrome (BRBNS) and a non-syndromic venous malformation. The level of mosaicism in the tissue ranged from 0.93% to 16.53%, with 60% (15/25) of the variants having ≥ 5% mosaicism. Three variant of uncertain significance of IDH1 and NACC1 were found and deserve further investigation for their pathogenic role. Data from the present study suggest the potential benefit of targeted therapy, in particular drugs in the mTOR pathway, for these patients.