Figure 1.
Flowchart of this multi-institutional study and graphical representation of DDX41 variants found in this study. (A) In this study, 195 (2%) patients with HM with at least 1 DDX41 variant (MAF < 0.1%) are identified in 9821 unrelated and unselected adult patients from 6 medical centers and at ARUP Laboratories. Among these patients with HM, 3583 are diagnosed with AML, 2160 with MDS, 1030 with MPN, and 3048 with others including cytopenia and other myeloid and lymphoid neoplasms. These DDX41 variants are further classified into somatic variants alone (variants with a VAF < 40% in isolation) and presumed germline variants (VAFs of 40% or above, with or without concurrent somatic DDX41 variants). The germline variants are further classified into CV (PV/LPV, n = 116) and VUS (n = 60), according to the proposed gene-specific diagnostic criteria, modified from the ACMG guidelines.20 Among the 116 patients with germline DDX41 CV, 66 are diagnosed with AML, 28 with MDS, 4 with MPN, and 18 with cytopenia (others). Similarly, among the 60 patients with germline VUS, 18 are diagnosed with AML, 12 with MDS, 11 with MPN, and 19 with others. Among others, 4 are diagnosed with B-cell LPD, 1 with MM, and 14 with cytopenia. In addition, we select 4307 adult patients with HM (age of 18 years or above) with wild-type DDX41 (DDX41−), confirmed by NGS testing at ARUP laboratories during the same time period. Among these control patients (DDX41−), 1365 have a documented AML diagnosis, and the remaining cases include 1109 MDS, 479 MPN, and 1354 others, most of which are cytopenia, similar to those in the cohort of 9821 patients described above. Patients’ age, sex, and cytogenetic and molecular profiles are summarized and sorted by each distinct MN entity and correlated with their DDX41 genotypes (short double-headed arrows indicate the epidemiologic and molecular profile comparisons in between DDX41+ CV, VUS, and DDX41− cohorts). Furthermore, we summarize the OS in patients with AML and MDS who were treated at Huntsman Cancer Institute and other medical centers in comparison with the age-matched cohorts (long double-headed arrows indicate the OS comparisons in between DDX41+ CV, VUS, and DDX41− cohorts). #Of note, 24 patients with AML with DDX41 CV have been documented in a previous study.8 (B) Graphic distribution of variants identified in this study, positioned on the protein sequence (NM_016222.4) with major functional domains (red, DEAD domain; green, helicase domain; orange, Znf, zinc finger domain; teal, NLS, nuclear localization signaling domain) is separated by germline (above-protein sequences) or somatic (below) variants. Each symbol in germline variants represents 1 patient. The underline indicates novel variants reported in this study. Red, DDX41 CV; blue, DDX41 VUS; orange, p.R164W, likely CV in lymphoma. *With specific exceptions (eg, p.M155I and p.P510S).

Flowchart of this multi-institutional study and graphical representation of DDX41 variants found in this study. (A) In this study, 195 (2%) patients with HM with at least 1 DDX41 variant (MAF < 0.1%) are identified in 9821 unrelated and unselected adult patients from 6 medical centers and at ARUP Laboratories. Among these patients with HM, 3583 are diagnosed with AML, 2160 with MDS, 1030 with MPN, and 3048 with others including cytopenia and other myeloid and lymphoid neoplasms. These DDX41 variants are further classified into somatic variants alone (variants with a VAF < 40% in isolation) and presumed germline variants (VAFs of 40% or above, with or without concurrent somatic DDX41 variants). The germline variants are further classified into CV (PV/LPV, n = 116) and VUS (n = 60), according to the proposed gene-specific diagnostic criteria, modified from the ACMG guidelines.20 Among the 116 patients with germline DDX41 CV, 66 are diagnosed with AML, 28 with MDS, 4 with MPN, and 18 with cytopenia (others). Similarly, among the 60 patients with germline VUS, 18 are diagnosed with AML, 12 with MDS, 11 with MPN, and 19 with others. Among others, 4 are diagnosed with B-cell LPD, 1 with MM, and 14 with cytopenia. In addition, we select 4307 adult patients with HM (age of 18 years or above) with wild-type DDX41 (DDX41−), confirmed by NGS testing at ARUP laboratories during the same time period. Among these control patients (DDX41−), 1365 have a documented AML diagnosis, and the remaining cases include 1109 MDS, 479 MPN, and 1354 others, most of which are cytopenia, similar to those in the cohort of 9821 patients described above. Patients’ age, sex, and cytogenetic and molecular profiles are summarized and sorted by each distinct MN entity and correlated with their DDX41 genotypes (short double-headed arrows indicate the epidemiologic and molecular profile comparisons in between DDX41+ CV, VUS, and DDX41− cohorts). Furthermore, we summarize the OS in patients with AML and MDS who were treated at Huntsman Cancer Institute and other medical centers in comparison with the age-matched cohorts (long double-headed arrows indicate the OS comparisons in between DDX41+ CV, VUS, and DDX41− cohorts). #Of note, 24 patients with AML with DDX41 CV have been documented in a previous study.8 (B) Graphic distribution of variants identified in this study, positioned on the protein sequence (NM_016222.4) with major functional domains (red, DEAD domain; green, helicase domain; orange, Znf, zinc finger domain; teal, NLS, nuclear localization signaling domain) is separated by germline (above-protein sequences) or somatic (below) variants. Each symbol in germline variants represents 1 patient. The underline indicates novel variants reported in this study. Red, DDX41 CV; blue, DDX41 VUS; orange, p.R164W, likely CV in lymphoma. *With specific exceptions (eg, p.M155I and p.P510S).

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