AI Article Synopsis
- Correctly interpreting germline RUNX1 variants is crucial for diagnosing and managing FPD/AML (familial platelet disorder/acute myeloid leukemia).
- The study highlights two families with significant FPD/AML characteristics that have missense variants at a crucial residue (Gly168), which are often misclassified as variants of unknown significance (VUS).
- Evidence from computational analysis and observed platelet expression suggests these variants are likely pathogenic, indicating a need to revise RUNX1 classification guidelines to improve diagnostic accuracy.
Article 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.
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| http://dx.doi.org/10.1111/bjh.19776 | DOI Listing |
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