Welcome to the Gene Scene! Each week, we will explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. Here, we focus on the condition that led to the gene’s inclusion on the list, providing clear, relevant information that supports your clinic. To subscribe to the Gene Scene, contact your local GSL or send a request to info@ambrygen.com. 

To access the Gene Scene archives, visit our blog. 

GENE SCENE SPOTLIGHT: This gene is not on the ACMG Secondary Findings List. However, given the definitive association with increased risks for hematologic malignancies, we wanted to spotlight this gene.

Clinical Phenotype Summary: 

The RUNX1 gene (NM_001754) is located on chromosome 21q22.12, encodes the runt-related transcription factor 1 protein and contains 8 coding exons. Pathogenic variants in this gene are known to cause RUNX1 familial platelet disorder with associated myeloid malignancies (RUNX1-FPDMM), which is inherited in an autosomal dominant fashion. 

RUNX1-FPDMM is characterized by:
•    Mild-to-moderate thrombocytopenia and platelet dysfunction, leading to easy bruising and prolonged bleeding. Severity of bleeding is highly variable and can range from subclinical to requiring blood transfusions. 
•    Some individuals may present with skin manifestations such as eczema or psoriasis. 

Pathogenic variants in RUNX1 also confer a significantly increased risk for hematologic malignancies, most commonly myelodysplastic syndrome and acute myeloid leukemia, though lymphoid malignancies are also reported in around a quarter of affected families. Age of onset can range from childhood to late adulthood. 

Lifetime risk for hematologic malignancies in individuals with RUNX1-FPDMM is estimated at 25-50%. However, variable expressivity is observed, and cancer risks will differ based on individual and family history.

Loss of function has been reported as the mechanism of disease for RUNX1-related FPDMM. 

Unique Considerations: 
Increased lifetime risk (25-50%) of hematologic malignancy exists when this variant is known to be of germline origin. Germline status should be confirmed in an alternate sample type (e.g. fibroblasts). 

Clinical Resources: 
Clinical Management Resource for RUNX1 and Understanding Your Positive RUNX1 Genetic Test Result

Citations: 

•    Brown AL et al. Semin Hematol.2017 Apr;54(2):60-69 PMID: 28637618
•    Deuitch N et al. Gene Reviews. 2021. PMID: 33661592 
•    Brown AL et al. Blood Adv. 2020 Mar 24;4(6):1131-1144 PMID: 32208489
•    Owen CJ et al. Blood. 2008 Dec 1;112(12):4639-45. PMID: 18723428
•    Sood R et al. Blood. 2017 Apr 13;129(15):2070-2082. PMID: 28179279
•    Badin MS et al. Haemophilia. 2017 May; 23(3):e204-e213. PMID: 28181366
•    Bluteau D et al. Blood. 2011 Dec 8;118(24):6310-20. PMID 21725049

Ambry Genetics Gene-Disease Validity Scheme

Each week, we explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. 

To learn more about the ACMG Secondary Findings list, click here.

To read all previous Gene Scene emails, click here.