DDX41-related hematologic malignancy predisposition syndrome

Summary

DDX41-related hematologic malignancy predisposition syndrome (MONDO:0014809) is a disease caused by DDX41 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DDX41 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 217

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	DDX41-related hematologic malignancy predisposition syndrome
Mondo ID	MONDO:0014809
OMIM	616871
Orphanet	488647
UMLS	C4225174
MedGen	895780
GARD	0017899
Is cancer (heuristic)	no

Also known as: DDX41 hereditary neoplastic syndrome · DDX41-related hematologic malignancy predisposition syndrome · hereditary neoplastic syndrome caused by mutation in DDX41 · MPLPF · myeloproliferative/lymphoproliferative neoplasms, familial (multiple types), susceptibility to

Data availability: 217 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › DDX41-related hematologic malignancy predisposition syndrome

Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, blue rubber bleb nevus, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, Rothmund-Thomson syndrome, mismatch repair cancer syndrome 1, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, Kostmann syndrome, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 3, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, colorectal cancer, susceptibility to, 12, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, nasopharyngeal carcinoma, susceptibility to, 3, familial isolated hyperparathyroidism, intestinal polyposis syndrome, dyskeratosis congenita, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, leukemia, acute myeloid, susceptibility to, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, CDH1-related diffuse gastric and lobular breast cancer syndrome, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, PALB2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, tumor predisposition syndrome 2, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

217 retrieved; paginated sample, class counts are floors:

102 uncertain significance, 50 conflicting classifications of pathogenicity, 20 likely pathogenic, 18 pathogenic/likely pathogenic, 17 pathogenic, 5 benign, 2 not provided, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069187	NM_016222.4(DDX41):c.305_306del (p.Lys102fs)	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1200681	NM_016222.4(DDX41):c.946_947del (p.Met316fs)	DDX41	Pathogenic	criteria provided, multiple submitters, no conflicts
1211430	NM_016222.4(DDX41):c.1141A>T (p.Lys381Ter)	DDX41	Pathogenic	criteria provided, multiple submitters, no conflicts
1312513	NM_016222.4(DDX41):c.1496dup (p.Ala500fs)	DDX41	Pathogenic	criteria provided, multiple submitters, no conflicts
1327658	NM_016222.4(DDX41):c.931C>T (p.Arg311Ter)	DDX41	Pathogenic	criteria provided, multiple submitters, no conflicts
1327775	NM_016222.4(DDX41):c.475C>T (p.Arg159Ter)	DDX41	Pathogenic	criteria provided, multiple submitters, no conflicts
1338492	NM_016222.4(DDX41):c.434+1G>C	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338505	NM_016222.4(DDX41):c.986del (p.Gln329fs)	DDX41	Pathogenic	criteria provided, single submitter
1338548	NM_016222.4(DDX41):c.1108C>T (p.Gln370Ter)	DDX41	Pathogenic	criteria provided, multiple submitters, no conflicts
1526312	NM_016222.4(DDX41):c.268C>T (p.Gln90Ter)	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1693456	NM_016222.4(DDX41):c.1105C>T (p.Arg369Ter)	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1800707	NM_016222.4(DDX41):c.847del (p.Leu283fs)	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1926322	NM_016222.4(DDX41):c.434+1G>A	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
210843	NM_016222.4(DDX41):c.415_418dup (p.Asp140delinsGlyTer)	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224636	NM_016222.4(DDX41):c.435-2_435-1delinsCA	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224637	NM_016222.4(DDX41):c.3G>A (p.Met1Ile)	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500216	NM_016222.4(DDX41):c.1603_1605delinsA (p.Phe535fs)	DDX41	Pathogenic	no assertion criteria provided
2500217	NM_016222.4(DDX41):c.1231-3C>G	DDX41	Pathogenic	no assertion criteria provided
2674794	NM_016222.4(DDX41):c.55G>T (p.Gly19Ter)	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674795	NM_016222.4(DDX41):c.1496del (p.Pro499fs)	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3368101	NM_016222.4(DDX41):c.804del (p.Glu268fs)	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3383194	NM_016222.4(DDX41):c.647dup (p.Ser217fs)	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3728424	NM_016222.4(DDX41):c.178del (p.Glu60fs)	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3766931	NM_016222.4(DDX41):c.434+1G>T	DDX41	Pathogenic	criteria provided, single submitter
3899306	NM_016222.4(DDX41):c.547T>A (p.Phe183Ile)	DDX41	Pathogenic	criteria provided, single submitter
3899311	NM_016222.4(DDX41):c.1621_1621+10del	DDX41	Pathogenic	criteria provided, single submitter
4056193	NM_016222.4(DDX41):c.2T>C (p.Met1Thr)	DDX41	Pathogenic	criteria provided, single submitter
4280624	NM_016222.4(DDX41):c.1301del (p.Pro434fs)	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
434917	NM_016222.4(DDX41):c.232_233insAA (p.Pro78fs)	DDX41	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
434918	NM_016222.4(DDX41):c.1142dup (p.Ile382fs)	DDX41	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DDX41	Definitive	Autosomal dominant	DDX41-related hematologic malignancy predisposition syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DDX41	Orphanet:488647	DDX41-related hematologic malignancy predisposition syndrome
DNAAF3	Orphanet:244	Primary ciliary dyskinesia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DDX41	HGNC:18674	ENSG00000183258	Q9UJV9	Probable ATP-dependent RNA helicase DDX41	gencc,clinvar
DNAAF3	HGNC:30492	ENSG00000167646	Q8N9W5	Dynein axonemal assembly factor 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DDX41	Probable ATP-dependent RNA helicase DDX41	Multifunctional protein that participates in many aspects of cellular RNA metabolism.
DNAAF3	Dynein axonemal assembly factor 3	Required for the assembly of axonemal inner and outer dynein arms.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DDX41	Other/Unknown	no		Helicase_C-like, DEAD/DEAH_box_helicase_dom, Helicase_ATP-bd
DNAAF3	Other/Unknown	no		DUF4470, DNAAF3_C, DNAAF3

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
lower esophagus mucosa	1
right frontal lobe	1
apex of heart	1
right testis	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DDX41	274	ubiquitous	marker	granulocyte, right frontal lobe, lower esophagus mucosa
DNAAF3	158	broad	marker	apex of heart, right uterine tube, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DDX41	2,388
DNAAF3	794

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DDX41	Q9UJV9	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAAF3	Q8N9W5	81.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
STING mediated induction of host immune responses	1	1038.2×	0.002	DDX41
IRF3-mediated induction of type I IFN	1	815.7×	0.002	DDX41
Regulation of innate immune responses to cytosolic DNA	1	761.3×	0.002	DDX41
mRNA Splicing - Major Pathway	1	54.6×	0.018	DDX41

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cGAS/STING signaling pathway	1	1685.2×	0.012	DDX41
axonemal dynein complex assembly	1	526.6×	0.013	DNAAF3
cerebrospinal fluid circulation	1	443.5×	0.013	DNAAF3
seminiferous tubule development	1	383.0×	0.013	DNAAF3
motile cilium assembly	1	290.6×	0.013	DNAAF3
cellular response to interferon-beta	1	263.3×	0.013	DDX41
determination of adult lifespan	1	216.1×	0.013	DNAAF3
determination of left/right symmetry	1	127.7×	0.020	DNAAF3
lung development	1	99.1×	0.022	DNAAF3
cell morphogenesis	1	78.8×	0.025	DNAAF3
multicellular organism growth	1	68.5×	0.026	DNAAF3
cell population proliferation	1	51.4×	0.032	DDX41
mRNA splicing, via spliceosome	1	45.8×	0.033	DDX41
brain development	1	39.8×	0.034	DNAAF3
heart development	1	39.4×	0.034	DNAAF3
defense response to virus	1	34.7×	0.036	DDX41
spermatogenesis	1	17.6×	0.066	DNAAF3
cell differentiation	1	14.6×	0.072	DDX41
apoptotic process	1	14.3×	0.072	DDX41
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	DDX41

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DDX41	1	2
DNAAF3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	DDX41

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DDX41	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	DDX41

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	DDX41
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DNAAF3

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DNAAF3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.