Functional analysis of germline RUNX1 variants identified in individuals with suspected familial platelet disorder

In vitro functional testing pipeline to reclassify germline *RUNX1* VUS

A comprehensive in vitro functional testing pipeline (reporter assays, EMSA, Western blot, immunofluorescence) was developed to evaluate 26 germline RUNX1 VUS identified in the NIH RUNX1 Natural History Study. Integration of functional data with allele frequencies and clinical data enabled reclassification of 17/26 variants (65%). The study identifies important limitations of current MM-VCEP guidelines, including overly stringent thresholds for some functionally impaired variants, and inadequate assays for RUNX1 C-terminal domain variants.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This functional classification pipeline applied to a rare but serious predisposition is exemplary. Reclassification of 65% of tested VUS is remarkable. The critiques of current MM-VCEP guidelines are well-founded and should feed into their revision. An important methodological contribution for teams managing FPDMM.