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Putative new childhood leukemia cancer predisposition syndrome caused by germline bi‐allelic missense mutations in DDX41
Author(s) -
Diness Birgitte R.,
Risom Lotte,
Frandsen Thomas L.,
Hansen Bente,
Andersen Mette K.,
Schmiegelow Kjeld,
Wadt Karin A. W.
Publication year - 2018
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22680
Subject(s) - missense mutation , exome sequencing , genetics , germline mutation , germline , biology , exome , mutation , allele , myeloid leukemia , leukemia , cancer research , gene
Abstract DDX41 has recently been identified as a new autosomal dominantly inherited cancer predisposition syndrome causing increased risk of adult onset acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We report for the first time compound heterozygote germline missense DDX41 mutations located in the DEAD‐box domain, identified in two siblings by exome sequencing. Both siblings have slight dysmorphic findings, psychomotor delays and intellectual disability, and one developed blastic plasmacytoid dendritic cell neoplasm (BPDCN) at age five. RNA‐sequencing of bone marrow showed DDX41 expression including both mutations. However, the allele fraction of p.Pro321Leu accounted for 96% in the RNA‐sequencing indicating this mutation to be the more significant variant. Exome sequencing of the leukemic blasts identified no additional known driver mutations. There is no pattern indicating autosomal dominantly inherited cancer predisposition in the family, but the father has sarcoidosis, which has been associated with heterozygous DDX41 mutation. We propose that bi‐allelic mutations in DDX41 could potentially be a new cancer predisposition syndrome associated with delayed psychomotor development.