Germline heterozygous DDX41 variants in a subset of familial myelodysplasia and acute myeloid leukemia

Myelodysplasia (MDS) and acute myeloid leukemia (AML) are mostly sporadic hematopoietic stem cell clonal disorders. However, there are rare occurrences of familial MDS/AML where there are two or more affected cases in the same family. To date, germline heterozygous mutations have been identified in 10 genes ( RUNX1 , CEBPA , TERC , TERT , GATA2 , SRP72 , ANKRD26 , ACD , ETV6 and DDX41 ) 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 associated with familial MDS/AML. Over the last 15 years we have accrued 78 families in which there are at least two cases of bone marrow failure and at least one of whom has MDS or AML. We have undertaken a combination of whole-exome and targeted sequencing to characterize these families. The targeted sequencing uses a newly designed familial MDS/AML gene panel that includes the above 10 listed genes. This analysis has enabled us to identify four families harboring heterozygous germline DDX41 (DEAD-box helicase 41) variants ( Figures 1a–d ); three families have novel frameshift variants (c.155dupA, c.1586_1587delCA and c.719delTinsCG) and the fourth family has a recurrent missense variant in the initiation codon (c.3G>A, rs141601766) described previously by Lewinsohn et al. 11 Collectively, these four families comprise seven cases of MDS and two cases of AML (age range, 40–70 years). These patients did not have any extra-hematopoietic features and therefore represent ‘pure’ MDS/AML ( Table 1 ). Figure 1 ( a – d ) Families with MDS–AML with variants in DDX41 , their age at diagnosis and their respective Sanger sequencing traces. Affected individuals are colored as follows: red, MDS; yellow, CML; black, AML; and green, other non-hematological cancer. ( e ) Schematic of DDX41 protein showing the heterozygous variants identified in this study. CML, chronic myeloid leukemia. Full size image Table 1 Characteristics and family history of index cases Full size table