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

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.

Insights into the involvement of spliceosomal mutations in myelodysplastic disorders from an analysis of SACY-1/DDX41 inCaenorhabditis elegans

“…While it is possible that the genetic properties of this mutation might differ between C. elegans and mammalian systems, it is worthwhile noting that the oncogenic variant must support the high levels of proliferation characteristic of neoplastic cells. While all the sacy-1 mutations we isolated in forward genetic screens occur at conserved amino acids, none of them match the oncogenic mutations thus far isolated (Polprasert et al 2015;Cardoso et al 2016;Lewinsohn et al 2016;Li et al 2016;Diness et al 2018 ;Sébert et al 2019). This observation is consistent with the idea that the oncogenic mutations are at most weakly antagonizing or weak reduction-of-function mutations, and thus would not have been isolated in forward genetic screens that require a substantial reduction in function.…”

“…The spliceosomal components frequently affected in MDS include the biochemically welldefined factors SF3B1, SRSF2, and U2AF1 (Yoshida et al 2011;reviewed by Yoshida and Ogawa 2014). More recent studies have implicated DDX41 (Ding et al 2012;Lewinsohn et al 2015;Polprasert et al 2015;Cardoso et al 2016;Li et al 2016;Diness et al 2018;reviewed by Maciejewski et al 2017), a DEAD-box RNA helicase highly conserved in metazoans, whose precise biochemical function in the spliceosome is less well understood. DDX41 appears to be specifically recruited to the catalytically active C complex (Jurica et al 2002;Bessonov et al 2008), which performs the second step of splicing in which the 5' and 3' exons are ligated and an intronic lariat is released.…”

“…Germline biallelic DDX41 missense mutations were recently reported in two siblings that exhibited intellectual disability, psychomotor delays, and facial and skeletal dysmorphologies, with one sibling presenting with childhood leukemia (Diness et al 2018). Other work suggests that DDX41 might be a multifunctional protein; in addition to its nuclear function in RNA splicing, it has been suggested to function as a cytoplasmic DNA sensor in a signaling pathway in the cytoplasm that detects infecting double stranded DNA and initiates an antiviral interferon response (Zhang et al 2011;Parvatiyar et al 2012;Stavrou et al 2015Stavrou et al , 2018reviewed by Jiang et al 2017).…”

Compound Heterozygous Variants in Pediatric Cancers: A Systematic Review

“…The sequencing methods used were highly variable across the studies ( Table 3 and Supplementary Data 1:T1). Of the studies in this review, 10 indicated that they used one or more forms of NGS sequencing (whole-exome, whole-genome, RNA-seq) and thus were able to sample CH variants broadly (Valentine et al, 2014;Spinella et al, 2015;Zhang et al, 2015Zhang et al, , 2018Diets et al, 2018;Diness et al, 2018;Gröbner et al, 2018;Waszak et al, 2018;Maciaszek et al, 2019;Schieffer et al, 2019). Thirteen studies indicated that they used non-NGS methods (Sanger, Direct sequencing, SNP-array, Multiplex ligation-dependent probe amplification) and were therefore limited in the number of genes and CH variants analyzed (Quesnel et al, 1999;De Rosa et al, 2000;Østergaard et al, 2005;Okkels et al, 2006;Scott et al, 2007;Herkert et al, 2011;Leenen et al, 2011;Chmara et al, 2013;Bakry et al, 2014;Piane et al, 2016;Svojgr et al, 2016;Moriyama et al, 2017;Sharapova et al, 2018).…”

“…Across all studies, cancer types with more than 10 samples included AML, ALL, high-grade glioma, medulloblastoma (Valentine et al, 2014;Zhang et al, 2015;Diets et al, 2018;Gröbner et al, 2018). Thirteen studies evaluated a single patient (Quesnel et al, 1999;De Rosa et al, 2000;Okkels et al, 2006;Scott et al, 2007;Peters et al, 2009;Majumdar et al, 2010;Chmara et al, 2013;Piane et al, 2016;Diness et al, 2018;Salih et al, 2018;Sharapova et al, 2018;Maciaszek et al, 2019;Schieffer et al, 2019).…”