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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Two novel families with RUNX1 variants indicate glycine 168 as a new mutational hotspot: Implications for FPD/AML
Laureano J Kamiya1, Serena Barozzi2, Federica Isidori3
1Hematology Research Division, Institute for Medical Research Alfredo Lanari, School of Medicine, University of Buenos Aires (UBA), Buenos Aires, Argentina.
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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