Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Experimental hematology	133		2024 May	104207	Exp Hematol

URL

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.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

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