DDX41

Gene Facts

• HGNC Symbol: DDX41 (HGNC:18674)
• HGNC Name: DEAD-box helicase 41
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: ABS, MGC8828
• %HI: 25.66
• pLI: 0
• LOEUF: 0.77
• Cytoband: 5q35.3
• Genomic Coordinates:

  GRCh37/hg19:	chr5:176938578-176943962
  GRCh38/hg38:	chr5:177511577-177516961

• MANE Select Transcript: NM_016222.4 ENST00000330503.12
• Function: Probable ATP-dependent RNA helicase. Is required during post- transcriptional gene expression. May be involved in pre-mRNA splicing. {ECO:0000269|PubMed:25920683}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-14058
• ClinGen Curation ID: CCID:006982
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 02/09/2022

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• DDX41-related hematologic malignancy predisposition syndrome

HI Evidence

• PUBMED: 25920683
  Polprasert et al (2015) in Cancer Cell reported a recurrent germline frameshift variant (p.Asp140Glufs*19 in exon 5/17 of DDX41) in seven unrelated families in which at least two individuals had various myeloid neoplasms. This variant and two other germline variants including one different truncating variant were detected in eight additional unrelated patients from a cohort of 1034 patients with a similar spectrum of disease. Somatic mutations acquired on the wild-type allele were detected in about half patients. In addition, eight patients from this cohort were found to carry a somatic variant in DDX41 and two of them were also found to have somatic deletion of 5q including this gene. DDX41 encodes an RNA helicase and RNA sequencing confirmed that DDX41 variants caused altered pre-mRNA splicing and RNA processing. RT-PCR demonstrated that deletions of this gene resulted in decreased mRNA expression. In vitro study suggested that decreased levels of DDX41 resulted in a higher sensitivity to growth factor stimuli compared to control. The study suggests that DDX41 constitutes a family of tumor suppressor genes since the disease requires both alleles to be inactivated, either with germline changes in this gene serving as a ‘‘first hit” and somatic mutations often coinciding as a second hit with the germline variants or two somatic changes. Overall, the study concludes that heterozygous germline DDX41 disease-causing variants convey a strong predisposition to a hereditary MDS/AML syndrome, which is characterized by long latency with protracted onset (between 44 and 70 years of age), advanced disease (high-risk MDS/AML), normal karyotype, and poor prognosis. The penetrance of this disease is incomplete which can explain genotype-positive and phenotype-negative scenarios in several families so BS4 (nonsegregation) cannot be applied.
• PUBMED: 31484648
  Sebert et al (2019; Blood) analyzed the prevalence and characteristics of DDX41-related myeloid malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted NGS analysis, the researchers identified 28 different germline DDX41 variants in 43 unrelated patients. Among 21 variants detected in 33 patients which were classified as causal, 13 (62%) were truncating variants (n=10) or variants affecting canonical splicing sites which are predicted to result in nonsense-mediated mRNA decay. The median age of onset in 33 patients with disease-causing variants was 69 years. The study highlights that germline DDX41 mutations are relatively common in adult MDS/AML, often without known family history. Salient features of DDX41-related myeloid malignancies include male preponderance, frequent preexisting cytopenia, additional somatic DDX41 mutation, and relatively good outcome.
• PUBMED: 30963592
  Quesada et al (2019; Am J Hematol) used a 81 gene NGS panel to identify DDX41 variants in 34 patients with myeloid neoplasms. Fifty-nine DDX41 variants were detected and 32% were germline identified from cultured skin biopsy. Most germline variants were upstream of the Helicase 2 domain, 28% of these variants involved loss of the start codon and 38% were truncating variants. The remaining 27 were somatic variants.
• PUBMED: 33585199
  Bannon et al., 2020 (Frontiers in Oncology) described 38 individuals with germline DDX41-mutated hematologic malignancies. All patients had at least one DDX41 mutation identified by NGS panel. These ranged from “hot-spot” germline DDX41 loss of function variants, p.D140fs*2, p.M1I, or p.Q41*. Splice site variants (c.434+1G>A) or missense variants (p.Gly218Asp, p.Met155Ile, p.I396T) (see Fig 1). Of note, there is relatively low penetrance and older age at onset of DDX41-related malignancy. Germline DDX41 mutations were typically associated with high grade neoplasms and diploid karyotype with relatively poor outcomes. Germline mutation carriers often present primarily with high-risk MDS and AML with MDS-related changes.
• PUBMED: 32868804
  Kim et al 2020 (Sci Reports) reported a frameshift (p.Ala500CysfsTer9; germline) DDX41 variant in one family member conferring susceptibility to familial myeloproliferative/lymphoproliferative neoplasms. This was done by NGS panel based testing and whole exome sequencing. The authors also note that DDX41 is one of most frequently detected germline predisposition mutations in myeloid malignancy, with around 70 families described to date. In these families, myeloid malignancies were again associated with normal karyotypes, and about 50% were found to have a somatic second hit mutation in DDX41. The authors also suggests that DDX41 acts as a tumor suppressor, as noted in other studies.
• PUBMED: 32098966
  Machin et al (Nature communications, 2020) reported start loss (p.Met1?) and stop loss (p.Arg124*) variants in DDX41. These were described in 2 unrelated families and no other associated non-hematological feature by targeted sequencing. They implicated DDX41 as a bona fide marker for inherited forms of AML/MDS.

• HI Evidence Comments: DECIPHER CNV entries are large and encompass DDX41 as well as adjacent genes. Focal deletions have not been reported in DECIPHER or DGV. However, loss of function variants, functional studies and segregation information provided by the studies listed above are noted for haploinsufficiency. Taken together, germline loss of function variation has been linked to haploinsufficiency for DDX41 and associated high-risk MDS and/or AML with MDS-related changes. Of note, PMID: 34723452 corresponds to the GeneReview entry for this condition.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: Focal duplications for DDX41 are not noted in primary literature. No evidence of triplosensitivity. Misc. comment: PMID 24819041: 5q35 microduplication encompassing NSD1 and DDX41 genes which have been reported at least in 30 cases presenting with delayed bone age, microcephaly, failure to thrive and seizures in some cases. NSD1 point mutations, submicroscopic deletions and intragenic deletions are the major cause of Sotos syndrome. Reverse clinical phenotype due to 5q35 microduplication further support a gene dosage effect of NSD1 on growth regulation and neurological functions.