Tamaryn J Knezovich¹, Jessica Wright¹, Rebecca Reid¹, Mark G Williams¹, Abhijit Kulkarni¹, Ronnie Tran¹, Martysse Rodgers¹, Jodie Fitness¹ , Polly Higgins², Karthik Rajah², Caroline McNamara³, Anna Brown^4,5, Helen Mar Fan³, Louise Seymour⁶, Edward Chew¹

¹Genomic Diagnostics, 460 Lower Heidelberg Road, Heidelberg, Victoria, 3084; ²QML Pathology, 11 Riverview Place, Murarrie, Queensland, 4172; ³Royal Brisbane and Women’s Hospital, Butterfield St, Herston, Queensland 4029; ⁴Department of Genetics and Molecular Pathology, SA Pathology, Frome Rd, Adelaide, South Australia 5000; ⁵Centre for Cancer Biology, SA Pathology and University of South Australia, Frome Rd, Adelaide, South Australia 5000; ⁶Pathology Queensland, Royal Brisbane and Women’s Hospital, Butterfield St, Herston, Queensland 4029

Background: Germline RUNX1 pathogenic variants predispose to familial platelet disorder with associated myeloid malignancies (RUNX1-FPDMM). This autosomal dominant condition is characterised by thrombocytopenia with an increased risk for MDS and AML (PMID: 37303296). We present a case where multiple testing modalities were utilised to confirm a germline RUNX1 variant.

Case: A 38-year-old male with progressive pancytopenia underwent a bone marrow examination. His father has MDS and sister has moderate cytopenias. A diagnosis of AML with NPM1 p.(Trp288Cysfs*12) and IDH1 p.(Arg132His) was made. The bone marrow sample massively parallel sequencing (MPS) also identified a monoallelic RUNX1 deletion  and it was confirmed by FISH. 

Discussion: The personal and family history prompted germline testing. A heterozygous 1.2Mbp deletion encompassing the entire RUNX1 {seq[GRCh37] del(21)(q22.12), chr21:g.36164371_37394832del} was detected, confirming the somatic MPS and FISH results as being of germline origin. 

Conclusion: Due to the variable penetrance and phenotypic heterogeneity, RUNX1-FPDMM can be asymptomatic until they present with malignant disease (PMID: 28179279). Our case highlights the pitfalls in focussing on only single nucleotide variants in somatic MPS. It is recommended that a comprehensive analysis that includes copy number analysis, on a non-haematological sample, is undertaken in young patients with MDS and AML (PMID: 28179279).