Clinical and molecular correlates of somatic and germline DDX41 variants in patients and families with myeloid neoplasms

The diagnosis of germline predisposition to myeloid neoplasms (MN) secondary to DDX41 variants is currently hindered by the long latency period, variable family histories and the frequent occurrence of DDX41 variants of uncertain significance (VUS). We reviewed 4,524 consecutive patients who underwent targeted sequencing for suspected or known MN and analyzed the clinical impact and relevance of DDX41(VUS) in comparison to DDX41(path) variants. Among 107 patients (44 [0.9%] DDX41(path) and 63 DDX41(VUS) [1.4%; 11 patients with both DDX41(path) and DDX41(VUS)]), we identified 17 unique DDX41(path) and 45 DDX41(VUS) variants: 24 (23%) and 77 (72%) patients had proven and presumed germline DDX41 variants, respectively. The median age was similar between DDX41(path) and DDX41(VUS) (66 vs. 62 years; P=0.41). The median variant allele frequency (VAF) (47% vs. 48%; P=0.62), frequency of somatic myeloid co-mutations (34% vs 25%; P= 0.28), cytogenetic abnormalities (16% vs. 12%; P=>0.99) and family history of hematological malignancies (20% vs. 33%; P=0.59) were comparable between the two groups. Time to treatment in months (1.53 vs. 0.3; P=0.16) and proportion of patients progressing to acute myeloid leukemia (14% vs. 11%; P=0.68), were similar. The median overall survival in patients with high-risk myelodysplastic syndrome/acute myloid leukemia was 63.4 and 55.7 months in the context of DDX41(path) and DDX41(VUS), respectively (P=0.93). Comparable molecular profiles and clinical outcomes among DDX41(path) and DDX41(VUS) patients highlights the need for a comprehensive DDX41 variant interrogation/classification system, to improve surveillance and management strategies in patients and families with germline DDX41 predisposition syndromes.