DEVELOPMENT OF A DATA PORTAL FOR AGGREGATION AND ANALYSIS OF GENOMICS DATA IN FAMILIAL PLATELET DISORDER WITH PREDISPOSITION TO MYELOID MALIGNANCY – THE RUNX1.DB

Abstract

Over 100 different families have been reported with damaging germline mutations or deletions in RUNX1, making it a clinically significant gene in FPD-MM. In large families, the diagnosis of haematological malignancy (HM) shows variable penetrance among members with the same mutation; some carriers do not develop HM. The cause of this heterogeneity is not yet understood but it is likely attributable to additional somatic genetic changes in these germline RUNX1 carriers. To better understand the genetic landscape surrounding RUNX1 germline predisposition to HM we have developed an interactive online database, the RUNX1 database ( https://runx1db.runx1.com ). This database is designed for the sharing and curation of genetic data acquired from individuals with germline RUNX1 mutation both pre- and post-HM progression. Currently we have collected 170 datasets from 11 countries. Raw NGS data files were transferred, preferentially as FASTQ files, and run through a standardised bioinformatics pipeline generating VCF and BAM files. These files were uploaded onto the RUNX1.db where the integrated VariantGrid, genomics analysis software, can be used to provide automated annotation of variants within the VCF files. Using the RUNX1db to curate variants from previously published and new datasets we have been able to confirm published somatic and germline mutations, and importantly, extend on these findings by identifying additional somatic mutations of clinical significance. Interrogating this dataset as a single cohort we have identified somatic genetic signatures in pre-leukemic samples prior progression to AML, including recurrent mutations in several clonal haematopoiesis genes including BCOR. This RUNX1 worldwide genomics cohort will lead to powerful insights in the development of precision-based medicine diagnosis, risk assessment, monitoring and therapeutic intervention.