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Case Reports
. 2024 Dec;205(6):2315-2320.
doi: 10.1111/bjh.19776. Epub 2024 Oct 7.

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

Laureano J Kamiya  1 , Serena Barozzi  2 , Federica Isidori  3 , Daiana Ganiewich  4   5 , Geraldine De Luca  1   6 , Valeria Bozzi  2 , Rosana F Marta  1   6 , Federica Melazzini  2   7 , Tommaso Pippucci  3 , Paula G Heller  1   6 , Ana C Glembotsky  1   6 , Alessandro Pecci  2   7
Affiliations
Case Reports

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

Laureano J Kamiya et al. Br J Haematol. 2024 Dec.

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.

Keywords: RUNX1; familial platelet disorder; inherited haematological malignancy; inherited platelet disorders; variant curation.

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References

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