DDX41: here, there…and everywhere

In this issue of Blood, Cheloor Kovilakam et al¹ report a comprehensive population-level analysis of >450 000 adults in the UK Biobank assessing the epidemiologic characteristics, clinical features, and malignancy risk associated with germ line pathogenic variants in the DEAD box RNA helicase 41 gene (DDX41-GPV).

The causal link between germ line genetic variants and predisposition to myeloid malignancies has been increasingly recognized in recent years, and pathogenic DDX41 variants represent one of the most significant germ line risk factors for myelodysplastic syndromes/acute myeloid leukemia (MDS/AML) in adults.² However, the overall prevalence and absolute risk of myeloid malignancies associated with individual DDX41 variants have not been systematically studied at the population level.

Cheloor Kovilakam et al identified 452 unique nonsynonymous germ line DDX41 variants in 3538 (1 in 129) individuals (see figure). The frequency of specific variants differed significantly across ancestry groups, with some occurring exclusively among Europeans (eg, p.M1? and p.D140Gfs∗2) or non-Europeans (eg, p.V412I and p.V412Gfs∗2). A subset of variants was classified as pathogenic (DDX41-GPV, n = 1059) if they result in loss of function (truncating, start-loss, canonical splice site mutation) or missense/in-frame indels that have been previously associated with a second somatic DDX41 mutation (frequently p.R525H). Consistent with prior studies,^3-5 individuals with DDX41-GPV were more likely to develop MDS/AML (odds ratio [OR], 12.3) associated with late disease onset (median age at diagnosis, 71 years), male predominance (OR, 4.15), and a family history of leukemia.

The biological mechanisms by which DDX41-GPV contribute to malignant transformation are not well understood. Cheloor Kovilakam et al found that the incidence of clonal hematopoiesis was similar between individuals with DDX41-GPV and controls. Furthermore, whole genome sequencing data revealed that the genome-wide mutation rate was not significantly different between DDX41-mutated and DDX41–wild type AML cases. DDX41-associated MDS/AML predominantly occurs via somatic acquisition of a second inactivating DDX41 mutation.^4-6 The authors found that presence of a second somatic DDX41 mutation and/or an elevated mean corpuscular volume were each predictive of progression to MDS/AML. Collectively, these data indicate that clonal selection and progression to MDS/AML among individuals with DDX41-GPV is biologically and prognostically distinct from sporadic MDS/AML.^2,4,6,7 

The analysis by Cheloor Kovilakam et al provides several novel and clinically relevant findings. First, the authors found that at the population level, the absolute risk of MDS/AML among adults (median age at recruitment, 58 years) with DDX41-GPV was 3.21% (males, 5.50%; females, 1.37%) over 13 years of follow-up. This included >450 000 adults from diverse ancestry backgrounds with minimal relatedness. Previous studies have reported a higher life-time risk of MDS/AML,⁴ which is likely due to analysis of first-degree relatives of patients with DDX41-mutated MDS/AML. Secondly, the authors demonstrate that the risk of MDS/AML is influenced by DDX41 variant type (truncating: OR, 15.1; start-loss: OR, 12.9; missense variants: OR, 7.5). Importantly, DDX41-GPV were not associated with risk of myeloproliferative neoplasms, lymphoid malignancies, other cancers, or autoimmune conditions. Lastly, a highly provocative finding from this study is that 1 in 430 individuals in the population have DDX41-GPV, which forces consideration of the rate of inadvertent donor-to-recipient transmission of DDX41-GPV from both related and unrelated stem cell donors.

How can these discoveries inform future research efforts and clinical management of patients with DDX41-GPV?

The American College of Medical Genetics (ACMG) criteria are the consensus standard for classifying germ line variants within any gene.⁸ Recently, more refined gene-specific and disease-associated variant criteria have been developed through the ClinGen Myeloid Malignancy Variant Curation Expert Panel.⁹ Cheloor Kovilakam et al propose that the cooccurrence of a somatic DDX41 mutation is a reliable pathogenic criterion for a germ line DDX41 missense variant that would otherwise be classified as a variant of uncertain significance by ACMG criteria. Such DDX41-specific variant classification rules that reflect known disease biology, as well as the development of robust functional assays, will greatly enhance the interpretation and clinical actionability of germ line DDX41 missense variants.

The optimal surveillance strategy of DDX41-GPV carriers is unknown; however, the analysis by Cheloor Kovilakam et al suggests that hematologic indices and somatic sequencing may identify individuals at higher risk of MDS/AML. Prospective longitudinal studies incorporating error-corrected DNA sequencing are needed to develop improved prognostic models and evidence-based surveillance recommendations for DDX41-GPV carriers. Lastly, the prospect of donor-to-recipient transmission of DDX41-GPV is concerning given the known risk of donor cell leukemia.¹⁰ Urgent registry-level studies are required to determine the impact of DDX41-GPV transmission on transplant outcomes. Indeed, this also raises additional questions regarding the utility and ethical considerations of routine DDX41 genotyping in the evaluation of transplant donors, which also warrant investigation.

In summary, the study by Cheloor Kovilakam et al significantly advances our understanding of the population prevalence and myeloid malignancy risk associated with DDX41-GPV. It also demonstrates the utility of leveraging existing population-scale genotype/phenotype data to address clinically relevant questions related to germ line predisposition to hematologic neoplasms.

Conflict-of-interest disclosure: The authors declare no competing financial interests.