Validation and clinical application of transactivation assays for RUNX1 variant classification

Melanie Decker, Anupriya Agarwal, Andreas Benneche, Jane Churpek, Nicolas Duployez, Adam Duvall, Martijn P.T. Ernst, Alisa Forster, Hildegunn Høberg-Vetti, Inga Hofmann, Michelle Nash, Marc H.G.P. Raaijmakers, Tor H.A. Tvedt, Adrianna Vlachos, Brigitte Schlegelberger, Thomas Illig, Tim Ripperger*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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Abstract

Familial platelet disorder with associated myeloid malignancies (RUNX1-familial platelet disorder [RUNX1-FPD]) is caused by heterozygous pathogenic germline variants of RUNX1. In the present study, we evaluate the applicability of transactivation assays to investigate RUNX1 variants in different regions of the protein. We studied 11 variants to independently validate transactivation assays supporting variant classification following the ClinGen Myeloid Malignancies Variant Curation Expert Panel guidelines. Variant classification is key for the translation of genetic findings. We showed that new assays need to be developed to assess C-terminal RUNX1 variants. Two variants of uncertain significance (VUS) were reclassified to likely pathogenic. Additionally, our analyses supported the (likely) pathogenic classification of 2 other variants. We demonstrated functionality of 4 VUS, but reclassification to (likely) benign was challenging and suggested the need for reevaluating current classification guidelines. Finally, clinical utility of our assays was illustrated in the context of 7 families. Our data confirmed RUNX1-FPD suspicion in 3 families with RUNX1-FPD-specific family history, whereas for 3 variants identified in RUNX1-FPD-nonspecific families, no functional defect was detected. Applying functional assays to support RUNX1 variant classification can be essential for adequate care of index patients and their relatives at risk. It facilitates translation of genetic data into personalized medicine.

Original languageEnglish
Pages (from-to)3195-3200
Number of pages6
JournalBlood advances
Volume6
Issue number11
DOIs
Publication statusPublished - 14 Jun 2022

Bibliographical note

Funding Information:
The project was funded by the European Hematology Association John Goldman Clinical Research Grant 2017 (T.R.) and the Research Network MyPred (01GM1911B) funded by the German Federal Ministry of Education and Research (M.D., A.F., T.I., and T.R.).

Publisher Copyright: © 2022 by The American Society of Hematology.

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