Putative new childhood leukemia cancer predisposition syndrome caused by germline bi-allelic missense mutations in DDX41

TY - JOUR

T1 - Putative new childhood leukemia cancer predisposition syndrome caused by germline bi-allelic missense mutations in DDX41

AU - Diness, Birgitte R.

AU - Risom, Lotte

AU - Frandsen, Thomas L.

AU - Hansen, Bente

AU - Andersen, Mette K.

AU - Schmiegelow, Kjeld

AU - Wadt, Karin A.W.

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - BPDCN

KW - cancer predisposition

KW - DDX41

KW - germline

U2 - 10.1002/gcc.22680

DO - 10.1002/gcc.22680

M3 - Journal article

C2 - 30144193

AN - SCOPUS:85054715927

SN - 1045-2257

VL - 57

SP - 670

EP - 674

JO - Genes, Chromosomes & Cancer

JF - Genes, Chromosomes & Cancer

IS - 12

ER -