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Ref Type Journal Article
PMID (38522505)
Authors Beckmann CCA, Ramamoorthy S, Trompouki E, Driever W, Schwarz-Furlan S, Strahm B, Yoshimi A, Niemeyer CM, Erlacher M, Kapp FG
Title Assessment of a novel NRAS in-frame tandem duplication causing a myelodysplastic/myeloproliferative neoplasm.
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Abstract Text Myelodysplastic/myeloproliferative diseases of childhood cause a relevant disease burden, and many of these diseases may have a fatal course. The use of next-generation sequencing (NGS) has led to the identification of novel genetic variants in patients with these diseases, advancing our understanding of the underlying pathophysiology. However, novel mutations can often only be interpreted as variants of unknown significance (VUS), hindering adequate diagnosis and the use of a targeted therapy. To improve variant interpretation and test targeted therapies in a preclinical setting, we are using a rapid zebrafish embryo model that allows functional evaluation of the novel variant and possible therapeutic approaches within days. Thereby, we accelerate the translation from genetic findings to treatment options. Here, we establish this workflow on a novel in-frame tandem duplication in NRAS (c.192_227dup; p.G75_E76insDS65_G75) identified by Sanger sequencing in a 2.5-year-old patient with an unclassifiable myelodysplastic/myeloproliferative neoplasm (MDS/MPN-U). We show that this variant results in a myeloproliferative phenotype in zebrafish embryos with expansion of immature myeloid cells in the caudal hematopoietic tissue, which can be reversed by MEK inhibition. Thus, we could reclassify the variant from likely pathogenic to pathogenic using the American College of Medical Genetics (ACMG) criteria.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
NRAS G75_E76insDSAMRDQYMRTG insertion loss of function - predicted NRAS G75_E76insDSAMRDQYMRTG results in the insertion of 12 amino acids in the Nras protein between amino acids 75 and 76 (UniProt.org). G75_E76insDSAMRDQYMRTG results in increased immature myeloid cells in a zebrafish model (PMID: 38522505), and therefore, is predicted to lead to a loss of Nras protein function resulting in activation of downstream signaling.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS G75_E76insDSAMRDQYMRTG myelodysplastic/myeloproliferative neoplasm sensitive Trametinib Preclinical Actionable In a preclinical study, Mekinist (trametinib) decreased the accumulation of immature myeloid cells in a zebrafish model of myelodysplastic/myeloproliferative neoplasm harboring NRAS G75_E76insDSAMRDQYMRTG (PMID: 38522505). 38522505
NRAS G75_E76insDSAMRDQYMRTG myelodysplastic/myeloproliferative neoplasm sensitive PD-0325901 Preclinical Actionable In a preclinical study, PD-0325901 decreased the accumulation of immature myeloid cells in a zebrafish model of myelodysplastic/myeloproliferative neoplasm harboring NRAS G75_E76insDSAMRDQYMRTG (PMID: 38522505). 38522505