Idiopathic aplastic anemia

Summary

Idiopathic aplastic anemia (MONDO:0012197) is a disease with 1 cohort gene (4 GWAS associations across 5 studies) and 19 clinical trials. Top therapeutic interventions include eltrombopag and fluphenazine decanoate.

At a glance

• Prevalence: 1-9 / 1 000 000 (Brazil) [Orphanet-validated]
• Cohort genes: 1
• GWAS associations: 4
• Phenotypes (HPO): 12
• Clinical trials: 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.27	Brazil	Validated
Point prevalence	1-9 / 1 000 000	0.4	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0001903	Anemia	Obligate (100%)
HP:0005528	Bone marrow hypocellularity	Very frequent (80-99%)
HP:0001896	Reticulocytopenia	Frequent (30-79%)
HP:0001876	Pancytopenia	Frequent (30-79%)
HP:0000225	Gingival bleeding	Occasional (5-29%)
HP:0000421	Epistaxis	Occasional (5-29%)
HP:0000573	Retinal hemorrhage	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0002719	Recurrent infections	Occasional (5-29%)
HP:0031364	Ecchymosis	Occasional (5-29%)
HP:0030057	Autoimmune antibody positivity	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	idiopathic aplastic anemia
Mondo ID	MONDO:0012197
MeSH	C538494
Orphanet	88
ICD-10-CM	D61.3
ICD-11	1615519452
NCIT	C61230
SNOMED CT	191256002
UMLS	C0348890
MedGen	87595
GARD	0005836
Is cancer (heuristic)	no

Also known as: anaemia aplastic · anemia aplastic · aplastic anaemia · aplastic anaemia idiopathic · aplastic anemia idiopathic · idiopathic aplastic aplasia · idiopathic bone marrow failure · secondary aplastic anaemia · secondary aplastic anemia

Data availability: 4 GWAS associations (5 studies) · 1 GenCC gene-disease record · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › aplastic anemia › idiopathic aplastic anemia

Related subtypes (3): inherited aplastic anemia, myelophthisic anemia, acquired aplastic anemia

Genetics & variants

GWAS landscape

4 GWAS associations across 5 studies. Top hits map to 4 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs738408	7e-19	PNPLA3	C	0.18
rs738409	6e-18	PNPLA3	C	0.19
rs77375493	2e-11	JAK2	G	1.34
rs2814778	3e-11	ACKR1, CADM3-AS1	T	0.45

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475783	Verma A	2024	5,555	441,465	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90475782	Verma A	2024	1,363	119,195	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90479969	Verma A	2024	1,363	119,195	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477454	Verma A	2024	601	58,845	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90435807	Zhou W	2018	436	390,026	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	2
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	1

MAF distribution

Bucket	Variants
common (>=0.05)	3
low_freq (0.01-0.05)	0
rare (<0.01)	1
unknown	0

Functional consequences

Consequence	Count
missense_variant	2
synonymous_variant	1
5_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs738408	22	43928850	C>A,G,T	0.224	synonymous_variant	PNPLA3	7e-19	Tier 4: intronic/intergenic
rs738409	22	43928847	C>A,G,T	0.225	missense_variant	PNPLA3	6e-18	Tier 1: coding
rs77375493	9	5073770	G>A,C,T	0	missense_variant	JAK2	2e-11	Tier 1: coding
rs2814778	1	159204893	T>A,C	0.175	5_prime_UTR_variant	ACKR1, CADM3-AS1	3e-11	Tier 2: splice/UTR

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · 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
NBN	Limited	Autosomal dominant	idiopathic aplastic anemia	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NBN	Orphanet:1331	Familial prostate cancer
NBN	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
NBN	Orphanet:647	Nijmegen breakage syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NBN	HGNC:7652	ENSG00000104320	O60934	Nibrin	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NBN	Nibrin	Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NBN	Other/Unknown	no		FHA_dom, BRCT_dom, SMAD_FHA_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cauda epididymis	1
endometrium epithelium	1
mammary duct	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NBN	299	ubiquitous	marker	endometrium epithelium, mammary duct, cauda epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NBN	1,989

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NBN	O60934	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. Enrichment computed across 1 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
Sensing of DNA Double Strand Breaks	1	1903.3×	0.008	NBN
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	951.7×	0.008	NBN
HDR through MMEJ (alt-NHEJ)	1	878.5×	0.008	NBN
Diseases of DNA Double-Strand Break Repair	1	815.7×	0.008	NBN
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	815.7×	0.008	NBN
Resolution of D-Loop Structures	1	634.4×	0.008	NBN
Diseases of DNA repair	1	571.0×	0.008	NBN
DNA Double Strand Break Response	1	475.8×	0.008	NBN
Impaired BRCA2 binding to PALB2	1	456.8×	0.008	NBN
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	423.0×	0.008	NBN
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	423.0×	0.008	NBN
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	423.0×	0.008	NBN
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	393.8×	0.008	NBN
Homologous DNA Pairing and Strand Exchange	1	380.7×	0.008	NBN
Homology Directed Repair	1	308.6×	0.008	NBN
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	308.6×	0.008	NBN
Impaired BRCA2 binding to RAD51	1	308.6×	0.008	NBN
Resolution of D-loop Structures through Holliday Junction Intermediates	1	300.5×	0.008	NBN
HDR through Single Strand Annealing (SSA)	1	292.8×	0.008	NBN
Meiosis	1	285.5×	0.008	NBN
Presynaptic phase of homologous DNA pairing and strand exchange	1	271.9×	0.008	NBN
DNA Double-Strand Break Repair	1	248.3×	0.008	NBN
Reproduction	1	190.3×	0.010	NBN
HDR through Homologous Recombination (HRR)	1	190.3×	0.010	NBN
Nonhomologous End-Joining (NHEJ)	1	167.9×	0.010	NBN
DNA Damage/Telomere Stress Induced Senescence	1	163.1×	0.010	NBN
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	146.4×	0.011	NBN
Cellular Senescence	1	137.6×	0.011	NBN
G2/M Checkpoints	1	134.3×	0.011	NBN
Regulation of TP53 Activity	1	132.8×	0.011	NBN

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
telomere maintenance via telomere trimming	1	8426.0×	0.002	NBN
telomeric 3’ overhang formation	1	4213.0×	0.002	NBN
negative regulation of telomere capping	1	3370.4×	0.002	NBN
blastocyst growth	1	2808.7×	0.002	NBN
protection from non-homologous end joining at telomere	1	2407.4×	0.002	NBN
DNA strand resection involved in replication fork processing	1	2106.5×	0.002	NBN
telomere maintenance in response to DNA damage	1	1872.4×	0.002	NBN
R-loop processing	1	1685.2×	0.002	NBN
double-strand break repair via alternative nonhomologous end joining	1	1685.2×	0.002	NBN
DNA double-strand break processing	1	1532.0×	0.002	NBN
homologous recombination	1	1404.3×	0.002	NBN
t-circle formation	1	1404.3×	0.002	NBN
regulation of DNA-templated DNA replication initiation	1	1053.2×	0.002	NBN
protein localization to site of double-strand break	1	1053.2×	0.002	NBN
isotype switching	1	842.6×	0.002	NBN
mitotic G2/M transition checkpoint	1	802.5×	0.002	NBN
positive regulation of telomere maintenance	1	510.7×	0.004	NBN
mitotic G2 DNA damage checkpoint signaling	1	443.5×	0.004	NBN
DNA damage checkpoint signaling	1	391.9×	0.004	NBN
positive regulation of double-strand break repair via homologous recombination	1	383.0×	0.004	NBN
neuroblast proliferation	1	366.4×	0.004	NBN
DNA damage response, signal transduction by p53 class mediator	1	358.6×	0.004	NBN
intrinsic apoptotic signaling pathway	1	358.6×	0.004	NBN
positive regulation of double-strand break repair	1	343.9×	0.004	NBN
neuromuscular process controlling balance	1	330.4×	0.004	NBN
telomere maintenance	1	267.5×	0.004	NBN
protein K63-linked ubiquitination	1	267.5×	0.004	NBN
meiotic cell cycle	1	244.2×	0.005	NBN
double-strand break repair	1	203.0×	0.005	NBN
double-strand break repair via homologous recombination	1	156.0×	0.007	NBN

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NBN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NBN	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NBN

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)
NBN	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 19.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	9
PHASE2	6
PHASE3	2
PHASE1/PHASE2	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06493981	PHASE3	NOT_YET_RECRUITING	Outcomes in Bone Marrow Aplasia.
NCT01163942	PHASE3	TERMINATED	Randomized Study In Severe Aplastic Anemia Patients Receiving Atg, Cyclosporin A, With Or Without G-CSF (SAA-G-CSF)
NCT05126849	PHASE2	RECRUITING	Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide in Patients With Acquired Refractory Aplastic Anemia or in Relapse After Immunosuppression
NCT05419843	PHASE2	NOT_YET_RECRUITING	Up-front Matched Unrelated Donor Transplantation in Pediatric Patients With Idiopathic Aplastic Anemia
NCT06607367	PHASE1/PHASE2	NOT_YET_RECRUITING	REscuing Bone Marrow Function in Patients with AplaStic AnaEmia and Bone Marrow FaiLure Post AllogEneiC Transplantation 2
NCT06769568	PHASE2	NOT_YET_RECRUITING	Reduced-dose Conditioning Regimen Containing TBI in HSCT Treating Elderly Patients With Aplastic Anemia
NCT06802055	PHASE2	RECRUITING	Efficacy and Safety of Sirolimus With or Without Cyclosporin A in Chinese Patients With Aplastic Anemia Refractory/Intolerant to Cyclosporin A
NCT07078721	PHASE2	NOT_YET_RECRUITING	Efficacy and Safety of UCBT With TMI -Based Conditioning Regimen for Adults With Refractory/Relapsed Aplastic Anemia
NCT01224496	PHASE1/PHASE2	COMPLETED	Traditional Chinese Medicine in the Supportive Management of Anaemic and Cytopenic (Leukopenia, Thrombocytopenia) Haematological Disorders
NCT03955601	PHASE2	UNKNOWN	A Novel TBI Free Conditioning Protocol for Haploidentical Transplant in Acquired Aplastic Anemia:
NCT07131878	Not specified	NOT_YET_RECRUITING	Assesment of Treatment Outcomes of Aquired Aplastic Anemia in Children : A Retrospective and Prospective Cohort
NCT07139600	Not specified	ACTIVE_NOT_RECRUITING	Multi-omics Profiling of Patients With Aplastic Anemia Before and After CD7-CAR-T Therapy
NCT07338422	Not specified	NOT_YET_RECRUITING	HID-HSCT Versus IST as First-line Treatment for SAA
NCT07461116	Not specified	RECRUITING	Adverse Effects of ATG/ALG Therapy in Aplastic Anemia
NCT07499284	Not specified	RECRUITING	A Multicenter, Randomized, Open-Label Study of Haplo-Cord HSCT for the Treatment of Aplastic Anemia
NCT07552506	Not specified	NOT_YET_RECRUITING	Clinical Study on the Preservation of Ovarian Function in Patients With Aplastic Anemia Following Allogeneic Hematopoietic Stem Cell Transplantation Using Goserelin
NCT01933035	Not specified	COMPLETED	Extended Platelet Parameters as a Means to Differentiate Immune Thrombocytopenia From Hypo-proliferative Thrombocytopenias.
NCT04761965	Not specified	UNKNOWN	Quantitative MRI of Bone Marrow Fat Fraction in Patients With Trepanobiopsy
NCT06837987	Not specified	COMPLETED	Modified Transplantation Regimen and aGVHD Prophylaxis for Severe Aplastic Anemia in the Setting of Allogeneic HSCT.

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ELTROMBOPAG	4	2
FLUPHENAZINE DECANOATE	4	1