PUBLICATION
Assessment of a novel NRAS in-frame tandem duplication causing a myelodysplastic/myeloproliferative neoplasm
- Authors
- Beckmann, C.C.A., Ramamoorthy, S., Trompouki, E., Driever, W., Schwarz-Furlan, S., Strahm, B., Yoshimi, A., Niemeyer, C.M., Erlacher, M., Kapp, F.G.
- ID
- ZDB-PUB-240325-3
- Date
- 2024
- Source
- Experimental hematology 133: 104207 (Journal)
- Registered Authors
- Driever, Wolfgang, Kapp, Friedrich, Trompouki, Eirini
- Keywords
- NRAS, myelodysplastic/myeloproliferative neoplasm, myeloproliferation, variant interpretation, variants of unknown significance (VUS), zebrafish model
- MeSH Terms
-
- Animals
- Child, Preschool
- Female
- GTP Phosphohydrolases*/genetics
- Gene Duplication
- High-Throughput Nucleotide Sequencing
- Humans
- Male
- Membrane Proteins*/genetics
- Myelodysplastic-Myeloproliferative Diseases*/genetics
- Tandem Repeat Sequences
- Zebrafish*/genetics
- PubMed
- 38522505 Full text @ Exp. Hematol.
Citation
Beckmann, C.C.A., Ramamoorthy, S., Trompouki, E., Driever, W., Schwarz-Furlan, S., Strahm, B., Yoshimi, A., Niemeyer, C.M., Erlacher, M., Kapp, F.G. (2024) Assessment of a novel NRAS in-frame tandem duplication causing a myelodysplastic/myeloproliferative neoplasm. Experimental hematology. 133:104207.
Abstract
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-years-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 ACMG criteria.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping