A germline PDGFRB splice site variant associated with infantile myofibromatosis and resistance to imatinib.
(2025) Genetics in Medicine — Vol. 27, n° 2, p. 101334 (2025)
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- Infantile myofibromatosis is characterized by the development of myofibroblastic tumors in young children. In most cases, the disease is caused by somatic gain-of-function variants in platelet-derived growth factor receptor beta (PDGFRB). Here, we report a novel germline intronic PDGFRB variant, c.2905-8G>A, in six unrelated infants with multifocal myofibromatosis and their relatives. We performed constitutional and tumor DNA and RNA sequencing to identify novel variants, which were subsequently characterized in cellular assays. All patients had multiple skin nodules, four had bone lesions and two had aggressive disease with bowel obstruction. The c.2905-8G>A substitution creates an alternative acceptor splice site in intron 21, inserting two codons in the PDGFRB transcript. Functional studies revealed that the splice change induced a partial loss of function, contrasting with previously-described variants. In four tumor samples, we identified a second somatic hit at position Asp850 in PDGFRB exon 18, triggering constitutive receptor activation and resistance to imatinib. In addition to vinblastine and methotrexate, two patients had received imatinib without objective response. One of them switched to dasatinib with concomitant improvement. This splice-site PDGFRB variant favors the development of myofibroma featuring an acquired oncogenic variant in the same gene and resistance to targeted therapy.
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Boulouadnine, B., Filser, M., Leducq, C., Losole, T., Bies, J., Smetsers, S., Kouwenberg, D., de Lange, I., Mensenkamp, A., Kordes, U. R., Minard-Colin, V., Orbach, D., Brichard, B., de Krijger, R., Masliah-Planchon, J., & Demoulin, J. B. (2025). A germline PDGFRB splice site variant associated with infantile myofibromatosis and resistance to imatinib. Genetics in Medicine, 27(2), 101334. https://doi.org/10.1016/j.gim.2024.101334 (Original work published 2025)