Somatic oncogenic events in Shwachman–Diamond syndrome: molecular genetic characterization and clinical significance

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Introduction. Shwachman–Diamond syndrome (SDS) is a hereditary bone marrow failure syndrome associated with an increased risk of myeloid neoplasms. Somatic genetic events play a significant role in the pathogenesis of malignant transformation in SDS; however, their clinical significance remains understudied. Aim. To study the spectrum of somatic genetic and cytogenetic changes in patients with SDS and their potential association with myeloid transformation. Materials and methods. The study included 41 patients with SDS. High-throughput sequencing using the “Clonality of Hematopoiesis” targeted gene panel and cytogenetic testing by fluorescence in situ hybridization were performed. The frequency, type, and variant allele frequency (VAF) of the somatic variants were analyzed. Results. Somatic transforming events were detected in 21.9% of the patients. Most commonly found were variants in the TP53 gene, mainly with low VAF and no signs of malignant transformation. Myeloid neoplasms developed in the presence of high-VAF mutations or alternative oncogenic events. Conclusion. The obtained data demonstrate the heterogeneity of myeloid transformation pathways in SDS and highlight the need for comprehensive molecular genetic testing in the clinical monitoring of affected patients.

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