Prevalence of cytopenia(s) and somatic variants in patients with <i>DDX41</i> mutant germline predisposition syndrome
Yael Kusne, Talha Badar, Terra L. Lasho, Ludovica Marando, Abhishek A. Mangaonkar, Christy M. Finke, James M. Foran, Aref Al‐Kali, Jeanne Palmer, Cecilia Y. Arana Yi, Hassan B. Alkhateeb, Naseema Gangat, David S. Viswanatha, Mark R. Litzow, Timothy M. Chlon, Alejandro Ferrer, Mrinal M. Patnaik
Abstract
Summary Germline variants in DDX41 ( DDX41 MT ‐germline predisposition syndrome [GPS]) are associated with predisposition to haematological malignancies (HM), including lymphoid and myeloid neoplasms (MN). We retrospectively analysed the clinical and molecular features of 195 patients diagnosed and treated at Mayo Clinic with DDX41 MT ‐GPS. Patients with germline DDX41 pathogenic variants (42.3%) and variants of unknown significance (VUS, 57.6%) were included. The median age was 68.6 years (16.2–93.4). Ninety‐two per cent were Caucasian, 64.1% were male and 30.8% had a family history of HM. There were 92 distinct germline variants among our cohort, and the most common was p.Met1? (15.9%), followed by p.Asp140Glyfs*2 (9.2%). Clinical diagnoses included asymptomatic carriers (10.2%), clonal cytopenia of undetermined significance (CCUS, 6.1%), myeloproliferative neoplasms (6.7%), myelodysplastic syndrome (40.5%), acute myeloid leukaemia (20.5%), lymphoid neoplasms (9.2%), plasma cell dyscrasias (6.1%) and solid tumours (22.5%). Patients with MN were older (median age 70 vs. 63.5 years) and more likely to be male (M:F ratio 2.3 vs. 1.0) and most patients (78.8%) with MN had a normal karyotype. The most common somatic variants involved DDX41 (34.4%), followed by TET2 (11.2%), DNMT3A (9.6%) and ASXL1 (9.2%). In summary, we have comprehensively described the spectrum of clinical phenotypes within the Mayo Clinic DDX41 MT ‐GPS cohort.