Novel Pathogenic Defects Of Dead/H-Box Helicases In Myeloid Neoplasms

Familial MDS is rare and usually associated with early presentation in childhood. We encountered identical twins presenting with concordant MDS (RCMD-subtype) and a strong family history of leukemia. Their diseases demonstrated several unifying features, including a clinical response to lenalidomide despite neither twin expressing the del(5q) abnormality, resulting in transfusion-independence and restoration of normal counts. Whole exome sequencing (WES) for confirmatory deep targeted sequencing identified the same somatic heterozygous missense mutation of DDX41, c.G1574A (p.R525H) in both cases. In addition, we found diversifying accessory somatic mutations; in case 1 the clonal architecture consisted of DDX41, PHF6 (c.59delG, p.C20fs) and DNMT3A (c.T1180C, p.C394R) in 45%, 14%, and 15% reads, respectively, while in the 2nd case the clone consisted of 37% DDX41 and 50% JAK2 (c.G1849T, p.V617F) mutant reads. We also found a rare non-synonymous alteration of DDX41, c.T1187C (p.I396T) present in the germline DNA in both twins (the prevalence of this germline minor allele in the general population is <.05%).