Hereditary Myelodysplastic Syndrome (MDS) / Acute Myeloid Leukemia (AML) via the DDX41 Gene

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias and hypercellular bone marrow. Progression of MDS to acute myeloid leukemia (AML) occurs in many patients- up to 40% in some studies (Heaney et al. 1999). MDS and AML are most often sporadic, late-onset malignancies, but recent data indicate that hereditary MDS/AML may have a higher incidence than was thought previously and may have a younger age of onset than sporadic cases (Churpek et al. 2015; Bannon and DiNardo 2016). MDS/AML are associated with several primary bone marrow failure disorders including Diamond-Blackfan anemia, Fanconi anemia, severe congenital neutropenia, Shwachman-Diamond syndrome, and dyskeratosis congenita (Owen et al. 2008, Auerbach 2009). Several additional MDS/AML predisposition syndromes have also been recognized that include clinical features such as pancytopenia, MonoMAC, and hearing loss (see Genetics). Not all cases of inherited MDS/AML are associated with prior conditions. Consequently, the presence of 'accessory' clinical features may increase suspicion of MDS/AML predisposition, but the absence of accessory phenotypes does not rule out an increased risk for MDS/AML.

Heterozygous variants in DDX41 have been identified in inherited and acquired forms of MDS/AML that are not necessarily associated with preceding clinical symptoms (Polprasert et al. 2015; Lewinsohn et al. 2016). A long latency period is associated with germline DDX41 variants and the average age of disease onset in patients from recent reports is > 60 years (Polprasert et al. 2015; Lewinsohn et al. 2016). The late onset of disease is similar to that found in sporadic cases of MDS/AML and may present a challenge for identifying carriers without previously identified affected family members. Approximately 50% of patients with germline variants in DDX41 acquire additional somatic DDX41 gene variants (Polprasert et al. 2015).

The DDX41 gene encodes an RNA helicase that may function during RNA splicing, though the exact gene function is uncertain. Cell-based assays indicate that loss of DDX41 function results in enhanced cell proliferation suggesting a tumor suppressor role for DDX41 (Polprasert et al. 2015). Pathogenic variants in DDX41 comprise primarily missense variants. Small insertions resulting in aberrant splicing or premature protein termination have also been reported in several patients, and a recurrent p.Asp140Glyfs*2 germline variant, consistent with a loss of protein function, was identified (Polprasert et al. 2015; Lewinsohn et al. 2016; Li et al. 2016).

In a recent study, either inherited or acquired DDX41 gene variants were found in 27 out of 1045 patients with myeloid neoplasms; 19 of these patients harbored germline DDX41 variants and ~ half of the 19 patients with germline variants also acquired somatic DDX41 variants (Polprasert et al. 2015).

This test provides full coverage of all coding exons of the DDX41 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

This test is designed for detecting germline variants and is not designed specifically for detecting low levels of acquired variants in somatic MDS/AML. Skin fibroblasts are the recommended specimen type for germline testing for MDS/AML; results from peripheral blood or bone marrow may confound interpretation (Nickels et al. 2013). However, when results are needed quickly for patient management decisions, buccal swab or saliva samples may be preferred.