Bone marrow failure syndrome

Summary

Bone marrow failure syndrome (MONDO:0000159) is a disease (an umbrella term covering 8 Mondo subtypes) with 6 cohort genes and 31 clinical trials. Top therapeutic interventions include fludarabine phosphate, 2-mercaptoethanesulfonic acid, and treosulfan.

At a glance

• Umbrella term: 8 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 3
• Clinical trials: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	bone marrow failure syndrome
Mondo ID	MONDO:0000159
MeSH	C536572
OMIM	614675
NCIT	C165614
UMLS	C2931245
MedGen	419754
GARD	0022719
Is cancer (heuristic)	no

Data availability: 3 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › bone marrow disorder › bone marrow failure syndrome

Related subtypes (6): osteomyelitis, bone marrow neoplasm, polycythemia, Fanconi anemia, Drachtman Weinblatt Sitarz syndrome, premature ovarian failure 15

Subtypes (8): autosomal dominant aplasia and myelodysplasia, pancytopenia-developmental delay syndrome, bone marrow failure syndrome 3, bone marrow failure syndrome 4, bone marrow failure syndrome 6, AMED syndrome, digenic, bone marrow failure syndrome 5, Ziegler-Huang syndrome

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

3 retrieved; paginated sample, class counts are floors:

3 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
134990	NM_002520.7(NPM1):c.476CTG[1] (p.Ala160del)	NPM1	Uncertain significance	criteria provided, single submitter
3958646	NM_001002800.3(SMC4):c.1925A>G (p.Tyr642Cys)	SMC4	Uncertain significance	criteria provided, multiple submitters, no conflicts
4056098	NM_001002800.3(SMC4):c.2478+3A>G	SMC4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 7 · 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
LCP1	Moderate	Autosomal dominant	bone marrow failure syndrome
MDM4	Moderate	Autosomal dominant	bone marrow failure syndrome	2
PTPN13	Moderate	Autosomal recessive	bone marrow failure syndrome
TOX4	Moderate	Autosomal dominant	bone marrow failure syndrome

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NPM1	Orphanet:1775	Dyskeratosis congenita
NPM1	Orphanet:300865	Primary cutaneous anaplastic large cell lymphoma
NPM1	Orphanet:402026	Acute myeloid leukemia with NPM1 somatic mutations
NPM1	Orphanet:520	Acute promyelocytic leukemia
NPM1	Orphanet:98833	Acute myeloblastic leukemia without maturation
NPM1	Orphanet:98834	Acute myeloblastic leukemia with maturation
NPM1	Orphanet:98842	Lymphomatoid papulosis

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TOX4	HGNC:20161	ENSG00000092203	O94842	TOX high mobility group box family member 4	gencc
LCP1	HGNC:6528	ENSG00000136167	P13796	Plastin-2	gencc
MDM4	HGNC:6974	ENSG00000198625	O15151	Protein Mdm4	gencc
PTPN13	HGNC:9646	ENSG00000163629	Q12923	Tyrosine-protein phosphatase non-receptor type 13	gencc
SMC4	HGNC:14013	ENSG00000113810	Q9NTJ3	Structural maintenance of chromosomes protein 4	clinvar
NPM1	HGNC:7910	ENSG00000181163	P06748	Nucleophosmin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TOX4	TOX high mobility group box family member 4	Transcription factor that modulates cell fate reprogramming from the somatic state to the pluripotent and neuronal fate.
LCP1	Plastin-2	Actin-binding protein.
MDM4	Protein Mdm4	Contributes to p53/TP53 regulation.
PTPN13	Tyrosine-protein phosphatase non-receptor type 13	Tyrosine phosphatase which negatively regulates FAS-induced apoptosis and NGFR-mediated pro-apoptotic signaling.
SMC4	Structural maintenance of chromosomes protein 4	Central component of the condensin complex, a complex required for conversion of interphase chromatin into mitotic-like condense chromosomes.
NPM1	Nucleophosmin	Involved in diverse cellular processes such as ribosome biogenesis, centrosome duplication, protein chaperoning, histone assembly, cell proliferation, and regulation of tumor suppressors p53/TP53 and ARF.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.17

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
Phosphatase	1	14.0×	0.208
Transcription factor	1	1.4×	0.539
Other/Unknown	4	1.2×	0.539

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TOX4	Other/Unknown	no		HMG_box_dom, HMG_box_dom_sf, TOX_HMG-box_domain
LCP1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, EF_hand_dom
MDM4	Transcription factor	no		Znf_RING, Znf_RanBP2, SWIB_MDM2_domain
PTPN13	Phosphatase	yes	3.1.3.48	PTP_cat, FERM_domain, Tyr_Pase_dom
SMC4	Other/Unknown	no		RecF/RecN/SMC_N, SMC_hinge, SMC
NPM1	Other/Unknown	no		Nucleoplasmin, Nucleoplasmin_core_dom, NPM1_C

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	2
ventricular zone	2
islet of Langerhans	1
olfactory bulb	1
leukocyte	1
monocyte	1
mononuclear cell	1
nipple	1
oocyte	1
mucosa of paranasal sinus	1
penis	1
urethra	1
embryo	1
ganglionic eminence	1
calcaneal tendon	1
left ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TOX4	290	ubiquitous	marker	colonic epithelium, olfactory bulb, islet of Langerhans
LCP1	228	ubiquitous	marker	monocyte, leukocyte, mononuclear cell
MDM4	270	ubiquitous	marker	nipple, oocyte, colonic epithelium
PTPN13	286	ubiquitous	marker	mucosa of paranasal sinus, urethra, penis
SMC4	271	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo
NPM1	276	ubiquitous	marker	calcaneal tendon, left ovary, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NPM1	7,589
SMC4	4,120
MDM4	3,431
PTPN13	2,354
LCP1	2,305
TOX4	1,993

Structural data

PDB: 6 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MDM4	O15151	39
PTPN13	Q12923	12
NPM1	P06748	8
LCP1	P13796	4
SMC4	Q9NTJ3	2
TOX4	O94842	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 46. Enrichment computed across 6 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation	1	456.8×	0.037	NPM1
Condensation of Prometaphase Chromosomes	1	207.6×	0.037	SMC4
ALK mutants bind TKIs	1	190.3×	0.037	NPM1
Stabilization of p53	1	152.3×	0.037	MDM4
p53-Dependent G1 DNA Damage Response	1	142.8×	0.037	MDM4
p53-Dependent G1/S DNA damage checkpoint	1	142.8×	0.037	MDM4
G1/S DNA Damage Checkpoints	1	134.3×	0.037	MDM4
Regulation of TP53 Activity through Methylation	1	108.8×	0.037	MDM4
TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain	1	103.8×	0.037	NPM1
Regulation of TP53 Expression and Degradation	1	103.8×	0.037	MDM4
Interleukin-37 signaling	1	103.8×	0.037	PTPN13
Cell Cycle	2	14.4×	0.037	SMC4, MDM4
Mitotic Prophase	1	73.7×	0.042	SMC4
Nuclear import of Rev protein	1	67.2×	0.042	NPM1
Oncogene Induced Senescence	1	67.2×	0.042	MDM4
Nuclear events stimulated by ALK signaling in cancer	1	65.3×	0.042	NPM1
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	1	60.1×	0.042	LCP1
Regulation of TP53 Degradation	1	58.6×	0.042	MDM4
RND1 GTPase cycle	1	53.1×	0.042	PTPN13
RND3 GTPase cycle	1	51.9×	0.042	PTPN13
RND2 GTPase cycle	1	51.9×	0.042	PTPN13
SUMOylation of transcription cofactors	1	48.6×	0.043	NPM1
Synthesis of PIPs at the plasma membrane	1	42.3×	0.047	PTPN13
SARS-CoV-1-host interactions	1	35.1×	0.054	NPM1
Deposition of new CENPA-containing nucleosomes at the centromere	1	31.7×	0.056	NPM1
Condensation of Prophase Chromosomes	1	31.3×	0.056	SMC4
Signaling by ALK fusions and activated point mutants	1	30.1×	0.056	NPM1
PKR-mediated signaling	1	28.2×	0.057	NPM1
Cellular Senescence	1	27.5×	0.057	MDM4
Regulation of TP53 Activity	1	26.6×	0.057	MDM4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of eIF2 alpha phosphorylation by dsRNA	1	2808.7×	0.012	NPM1
regulation of mRNA stability involved in cellular response to UV	1	2808.7×	0.012	NPM1
negative regulation of excitatory synapse assembly	1	1404.3×	0.012	PTPN13
positive regulation of cell cycle G2/M phase transition	1	936.2×	0.012	NPM1
meiotic chromosome segregation	1	702.2×	0.012	SMC4
positive regulation of centrosome duplication	1	561.7×	0.012	NPM1
negative regulation of centrosome duplication	1	561.7×	0.012	NPM1
negative regulation of protein kinase activity by regulation of protein phosphorylation	1	561.7×	0.012	NPM1
kinetochore organization	1	561.7×	0.012	SMC4
meiotic chromosome condensation	1	468.1×	0.012	SMC4
regulation of intracellular protein transport	1	468.1×	0.012	LCP1
positive regulation of protein localization to nucleolus	1	468.1×	0.012	NPM1
ribosomal large subunit export from nucleus	1	401.2×	0.012	NPM1
ribosomal small subunit export from nucleus	1	351.1×	0.012	NPM1
RNA polymerase II promoter clearance	1	351.1×	0.012	TOX4
atrial septum development	1	351.1×	0.012	MDM4
regulation of DNA damage response, signal transduction by p53 class mediator	1	351.1×	0.012	NPM1
positive regulation of chromosome condensation	1	351.1×	0.012	SMC4
ribosome assembly	1	312.1×	0.012	NPM1
actin filament network formation	1	312.1×	0.012	LCP1
protein stabilization	2	22.3×	0.012	MDM4, NPM1
regulation of centriole replication	1	280.9×	0.012	NPM1
positive regulation of chromosome separation	1	280.9×	0.012	SMC4
heart valve development	1	255.3×	0.013	MDM4
obsolete protein kinase A signaling	1	234.1×	0.013	LCP1
cellular response to toxic substance	1	234.1×	0.013	PTPN13
positive regulation of chromosome segregation	1	216.1×	0.013	SMC4
atrioventricular valve morphogenesis	1	200.6×	0.013	MDM4
actin crosslink formation	1	200.6×	0.013	LCP1
negative regulation of signal transduction by p53 class mediator	1	200.6×	0.013	MDM4

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 3

Druggability breadth: 6 of 6 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MDM4	DIOSMIN
NPM1	CERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MDM4	7	4
NPM1	5	4
SMC4	1	2
TOX4	0	0
LCP1	0	0
PTPN13	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DIOSMIN	4	MDM4
VERTEPORFIN	4	MDM4
CERITINIB	4	NPM1
BOSUTINIB	4	NPM1
CRIZOTINIB	4	NPM1
SIREMADLIN	2	MDM4
ALLICIN	2	MDM4
MOLIBRESIB	2	NPM1, SMC4
SAR-405838	1	MDM4
CGM-097	1	MDM4
ABT 737	1	MDM4
ASP-3026	1	NPM1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MDM4	149	Binding:148, Functional:1
NPM1	113	Binding:108, Functional:5
PTPN13	23	Binding:22, ADMET:1
LCP1	13	Binding:13
SMC4	7	Binding:7
TOX4	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PTPN13	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MDM4	149
NPM1	113

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

12 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)
DIOSMIN	4	MDM4
VERTEPORFIN	4	MDM4
CERITINIB	4	NPM1
BOSUTINIB	4	NPM1
CRIZOTINIB	4	NPM1
SIREMADLIN	2	MDM4
ALLICIN	2	MDM4
MOLIBRESIB	2	NPM1, SMC4
SAR-405838	1	MDM4
CGM-097	1	MDM4
ABT 737	1	MDM4
ASP-3026	1	NPM1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	MDM4, NPM1
B	Phased (≥1) drug, not yet approved	1	SMC4
C	Druggable family + PDB, no drug	1	PTPN13
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	TOX4, LCP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TOX4	6	—
LCP1	13	—
PTPN13	23	—

Clinical trials & evidence

Clinical trials

Clinical trials: 31.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	10
Not specified	8
PHASE1/PHASE2	6
PHASE3	3
EARLY_PHASE1	3
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00774527	PHASE3	COMPLETED	Comparison of Cy-Atg Vs Cy-Flu-Atg for the Conditioning Therapy in Allo-HCT
NCT02393508	PHASE3	UNKNOWN	The Impact of Red Cell Age on Product Utilization in the Chronically Transfused Outpatient Population
NCT06940570	PHASE3	SUSPENDED	Methadone as an Alternative Treatment for Children Underdoing HSCT
NCT01966367	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	CD34+ (Non-Malignant) Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation
NCT03128996	PHASE1/PHASE2	RECRUITING	Reduced Intensity Conditioning and Familial HLA-Mismatched BMT for Non-Malignant Disorders
NCT04356469	PHASE2	RECRUITING	TCR Alpha Beta T-cell Depleted Haploidentical HCT in the Treatment of Non-Malignant Hematological Disorders in Children
NCT04558736	PHASE2	RECRUITING	Haploidentical HCT for Severe Aplastic Anemia
NCT01050439	PHASE2	TERMINATED	Unrelated Donor Transplant for Malignant and Non-Malignant Disorders
NCT01419704	PHASE1/PHASE2	WITHDRAWN	Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies
NCT01596699	PHASE2	TERMINATED	Pilot Trial of Clofarabine Added to Standard Busulfan and Fludarabine for Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation
NCT01757145	PHASE2	UNKNOWN	Eltrombopag for Enhancing Platelet Engraftment in Adult Patients Undergoing Cord Blood Transplantation
NCT02055456	PHASE1/PHASE2	COMPLETED	Nandrolone Decanoate in the Treatment of Telomeropathies
NCT02224872	PHASE2	COMPLETED	Transplantation of Partially Mismatched Related or Matched Unrelated Bone Marrow for Patients With Refractory Severe Aplastic Anemia
NCT02277639	PHASE2	COMPLETED	Reduced Intensity Conditioning Using CD3+/CD19+ Depletion for Non Malignant Transplantable Diseases
NCT02337595	PHASE1/PHASE2	COMPLETED	Memory T-cell Infusion to Improve Immunity After TCR-alpha/Beta Depleted Hematopoietic Stem Cell Transplantation
NCT02349906	PHASE2	COMPLETED	Treosulfan-based Versus Busulfan-based Conditioning in Paediatric Patients With Non-malignant Diseases
NCT02722668	PHASE2	COMPLETED	UCB Transplant for Hematological Diseases Using a Non Myeloablative Prep
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT04965597	PHASE2	COMPLETED	Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)
NCT07585136	PHASE1	NOT_YET_RECRUITING	Stem Cell Mobilization and Apheresis for Life-threatening Blood Disorders
NCT02356653	EARLY_PHASE1	RECRUITING	Expanded Access Protocol Using CD3+/CD19+ Depleted PBSC
NCT02928991	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Fludarabine Based RIC for Bone Marrow Failure Syndromes
NCT06787560	EARLY_PHASE1	RECRUITING	CD7 CAR-T Cell Sequential Allo-HSCT for Non-malignant Blood and Immune System Diseases
NCT02720679	Not specified	RECRUITING	Investigation of the Genetics of Hematologic Diseases
NCT02958462	Not specified	RECRUITING	Pre-myeloid Cancer and Bone Marrow Failure Clinic Study
NCT03145545	Not specified	AVAILABLE	Expanded Access Protocol Using Alpha/Beta T and CD19+ Depleted PBSC
NCT04781790	Not specified	RECRUITING	French National Registry of Bone Marrow Failures
NCT05236764	Not specified	ACTIVE_NOT_RECRUITING	Haploidentical Hematopoietic Cell Transplantation Using TCR Alpha/Beta and CD19 Depletion
NCT00315419	Not specified	UNKNOWN	Identifying Characteristics of Bone Marrow Failure Syndromes
NCT00897260	Not specified	COMPLETED	Umbilical Cord Blood Transplantation As Treatment Of Adult Patients With Hematologic Disorders
NCT04819607	Not specified	UNKNOWN	The Evaluating Multidisciplinary Bone Marrow Failure Care in Bone Marrow Failure and Related Disorders.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLUDARABINE PHOSPHATE	4	5
2-MERCAPTOETHANESULFONIC ACID	4	2
TREOSULFAN	4	2
CLOFARABINE	4	1
ELTROMBOPAG	4	1
NANDROLONE DECANOATE	4	1