Two novel families with <i>RUNX1</i> variants indicate glycine 168 as a new mutational hotspot: Implications for FPD/AML diagnosis

Correct interpretation of the pathogenicity of germline RUNX1 variants is essential for FPD/AML diagnosis, clinical management and leukaemia surveillance. We report two families with clear FPD/AML phenotypic features harbouring missense variants at RHD critical residue Gly168. Although classified as of unknown significance (VUS) by RUNX1-specific curation guidelines, these variants should rather be considered likely pathogenic, as supported by computational tools, structural modelling and dysregulated platelet expression of RUNX1-targets, adding Gly168 among amino acids currently recognised as mutational hotspots. Our data could help reduce the number of variants classified as VUS, providing evidence for updating RUNX1 guidelines, thus improving FPD/AML diagnosis.

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Publication Details

Journal
British Journal of Haematology
Published
2024-10-07
DOI
https://doi.org/10.1111/bjh.19776
Citations
3
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
1.36

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article

Two novel families with RUNX1 variants indicate glycine 168 as a new mutational hotspot: Implications for FPD/AML diagnosis

Daiana Ganiewich, Geraldine De Luca, Federica Isidori, Paula G. Heller et al.
3 citations
British Journal of Haematology
Acute Myeloid Leukemia Research
1.36
article

Two novel families with RUNX1 variants indicate glycine 168 as a new mutational hotspot: Implications for FPD/AML diagnosis

Daiana Ganiewich, Geraldine De Luca, Federica Isidori, Paula G. Heller, Ana C. Glembotsky, Valeria Bozzi, Tommaso Pippucci, Serena Barozzi, Rosana F. Marta, Alessandro Pecci, Federica Melazzini, Laureano J. Kamiya
article en
3 citations

Abstract

Correct interpretation of the pathogenicity of germline RUNX1 variants is essential for FPD/AML diagnosis, clinical management and leukaemia surveillance. We report two families with clear FPD/AML phenotypic features harbouring missense variants at RHD critical residue Gly168. Although classified as of unknown significance (VUS) by RUNX1-specific curation guidelines, these variants should rather be considered likely pathogenic, as supported by computational tools, structural modelling and dysregulated platelet expression of RUNX1-targets, adding Gly168 among amino acids currently recognised as mutational hotspots. Our data could help reduce the number of variants classified as VUS, providing evidence for updating RUNX1 guidelines, thus improving FPD/AML diagnosis.

British Journal of HaematologyVol. 205(6)
Consejo Nacional de Investigaciones Científicas y Técnicas (AR), Austral University (AR), Universidad de Buenos Aires (AR), University of Pavia (IT), Fundación Instituto Leloir (AR), Institute for Medical Research (AR), Policlinico San Matteo Fondazione (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University of Bologna (IT)
Fondazione IRCCS Policlinico San Matteo, Ministero della Salute, Fondation Nelia et Amadeo Barletta, Fondo para la Investigación Científica y Tecnológica
Openalex Percentile: Top 17%
Acute Myeloid Leukemia Research
1.36
DOIOpen Access PDFOpenAlex
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