Beta-thalassemia major

Summary

Beta-thalassemia major (MONDO:0016486) is a disease with 1 cohort gene and 28 clinical trials. Top therapeutic interventions include mycophenolate mofetil, deferasirox, and deferiprone.

At a glance

• Prevalence: >1 / 1000 (Bahrain) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 7
• Phenotypes (HPO): 50
• Clinical trials: 28

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	>1 / 1000	160	Bahrain	Validated
Point prevalence	1-5 / 10 000	40	Oman	Validated
Prevalence at birth	1-9 / 1 000 000	0.7	United States	Validated

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000980	Pallor	Very frequent (80-99%)
HP:0004823	Anisopoikilocytosis	Very frequent (80-99%)
HP:0004840	Hypochromic microcytic anemia	Very frequent (80-99%)
HP:0010972	Anemia of inadequate production	Very frequent (80-99%)
HP:0011904	Persistence of hemoglobin F	Very frequent (80-99%)
HP:0011905	Reduced hemoglobin A	Very frequent (80-99%)
HP:0025066	Decreased mean corpuscular volume	Very frequent (80-99%)
HP:0025547	Decreased mean corpuscular hemoglobin concentration	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0000953	Hyperpigmentation of the skin	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001971	Hypersplenism	Frequent (30-79%)
HP:0001978	Extramedullary hematopoiesis	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)
HP:0006487	Bowing of the long bones	Frequent (30-79%)
HP:0009004	Hypoplasia of the musculature	Frequent (30-79%)
HP:0011031	Abnormality of iron homeostasis	Frequent (30-79%)
HP:0011842	Abnormality of skeletal morphology	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0000582	Upslanted palpebral fissure	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0000823	Delayed puberty	Occasional (5-29%)
HP:0000829	Hypoparathyroidism	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0001394	Cirrhosis	Occasional (5-29%)
HP:0001395	Hepatic fibrosis	Occasional (5-29%)
HP:0001433	Hepatosplenomegaly	Occasional (5-29%)
HP:0001644	Dilated cardiomyopathy	Occasional (5-29%)
HP:0001722	High-output congestive heart failure	Occasional (5-29%)
HP:0001954	Recurrent fever	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0002829	Arthralgia	Occasional (5-29%)
HP:0004936	Venous thrombosis	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0010620	Malar prominence	Occasional (5-29%)
HP:0031035	Chronic infection	Occasional (5-29%)
HP:0040075	Hypopituitarism	Occasional (5-29%)
HP:0200042	Skin ulcer	Occasional (5-29%)
HP:0430028	Hyperplasia of the maxilla	Occasional (5-29%)
HP:0000846	Adrenal insufficiency	Very rare (<1-4%)
HP:0001402	Hepatocellular carcinoma	Very rare (<1-4%)
HP:0011675	Arrhythmia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	beta-thalassemia major
Mondo ID	MONDO:0016486
Orphanet	231214
DOID	DOID:0080771
NCIT	C129699
SNOMED CT	26682008
UMLS	C0002875
MedGen	283
GARD	0017162
Is cancer (heuristic)	no

Also known as: Beta thalassemia Major · Cooley anaemia · Cooley anemia · Cooley’s Anaemia · Cooley’s Anemia · Mediterranean anaemia · Mediterranean anemia

Data availability: 7 ClinVar variants · 1 GenCC gene-disease record · 73 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited hemoglobinopathy › thalassemia › beta thalassemia › beta-thalassemia HBB/LCRB › beta-thalassemia major

Related subtypes (2): beta-thalassemia intermedia, thalassemia minor

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

7 retrieved; paginated sample, class counts are floors:

6 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
15234	NM_000518.4(HBB):c.92G>C (p.Arg31Thr)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15447	NM_000518.5(HBB):c.92+5G>C	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15454	NM_000518.5(HBB):c.93-21G>A	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15458	NM_000518.5(HBB):c.316-197C>T	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
21190	NM_000518.5(HBB):c.316-2A>C	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
439166	NM_000518.5(HBB):c.93-1G>C	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
982010	NC_000011.10:g.5225256_5225875delinsTCTACTT	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 33 · Orphanet: 29 · 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
HBB	Definitive	Semidominant	beta-thalassemia HBB/LCRB	33

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HBB	Orphanet:2132	Hemoglobin C disease
HBB	Orphanet:2133	Hemoglobin E disease
HBB	Orphanet:231214	Beta-thalassemia major
HBB	Orphanet:231222	Beta-thalassemia intermedia
HBB	Orphanet:231226	Unstable beta globin chain variant disease
HBB	Orphanet:231237	Delta-beta-thalassemia
HBB	Orphanet:231242	Hemoglobin C-beta-thalassemia syndrome
HBB	Orphanet:231249	Hemoglobin E-beta-thalassemia syndrome
HBB	Orphanet:232	Sickle cell anemia
HBB	Orphanet:247511	Autosomal dominant secondary polycythemia
HBB	Orphanet:251365	Sickle cell S-C disease
HBB	Orphanet:251370	Sickle cell S-D Punjab disease
HBB	Orphanet:251375	Sickle cell S-E disease
HBB	Orphanet:251380	Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
HBB	Orphanet:330041	Hemoglobin M disease
HBB	Orphanet:46532	Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
HBB	Orphanet:695140	Sickle cell-beta zero-thalassemia
HBB	Orphanet:695147	Sickle cell-beta plus-thalassemia
HBB	Orphanet:699822	Sickle cell S-Lepore disease
HBB	Orphanet:700090	Sickle cell S-O Arab disease
HBB	Orphanet:700107	Sickle cell S-other specified hemoglobin variant
HBB	Orphanet:700111	Homozygous hemoglobin O Arab disease
HBB	Orphanet:715125	Hemoglobin E-beta-thalassemia intermedia
HBB	Orphanet:715128	Hemoglobin E-beta-thalassemia major
HBB	Orphanet:715135	Hemoglobin Lepore-beta-thalassemia intermedia
HBB	Orphanet:715140	Hemoglobin Lepore-beta-thalassemia major
HBB	Orphanet:715143	Heterozygous beta-thalassemia intermedia with supernumerary alpha-globin gene
HBB	Orphanet:715157	Low oxygen affinity beta chain hemoglobin disease
HBB	Orphanet:90039	Hemoglobin D disease

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
HBB	HGNC:4827	ENSG00000244734	P68871	Hemoglobin subunit beta	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HBB	Hemoglobin subunit beta	Involved in oxygen transport from the lung to the various peripheral tissues.

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)
HBB	Other/Unknown	no		Globin, Hemoglobin_b, Globin-like_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
monocyte	1
trabecular bone tissue	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HBB	284	broad	marker	monocyte, trabecular bone tissue, vena cava

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HBB	454

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HBB	P68871	350

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Heme assimilation	1	3806.7×	0.003	HBB
Erythrocytes take up oxygen and release carbon dioxide	1	1268.9×	0.003	HBB
Erythrocytes take up carbon dioxide and release oxygen	1	878.5×	0.003	HBB
Scavenging of heme from plasma	1	878.5×	0.003	HBB
Chaperone Mediated Autophagy	1	496.5×	0.004	HBB
Late endosomal microautophagy	1	326.3×	0.005	HBB
Heme signaling	1	215.5×	0.007	HBB
Cytoprotection by HMOX1	1	184.2×	0.007	HBB
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.017	HBB
Neutrophil degranulation	1	23.1×	0.043	HBB

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
nitric oxide transport	1	3370.4×	0.002	HBB
cellular oxidant detoxification	1	1872.4×	0.002	HBB
renal absorption	1	1685.2×	0.002	HBB
carbon dioxide transport	1	1296.3×	0.002	HBB
oxygen transport	1	1053.2×	0.002	HBB
hydrogen peroxide catabolic process	1	674.1×	0.003	HBB
blood vessel diameter maintenance	1	624.1×	0.003	HBB
erythrocyte development	1	526.6×	0.003	HBB
response to hydrogen peroxide	1	468.1×	0.003	HBB
positive regulation of nitric oxide biosynthetic process	1	455.5×	0.003	HBB
platelet aggregation	1	337.0×	0.004	HBB
regulation of blood pressure	1	221.7×	0.005	HBB
inflammatory response	1	37.7×	0.027	HBB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
HBB	CANDESARTAN CILEXETIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HBB	23	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANDESARTAN CILEXETIL	4	HBB
MECHLORETHAMINE HYDROCHLORIDE	4	HBB
PHENAZOPYRIDINE HYDROCHLORIDE	4	HBB
MERCAPTOPURINE ANHYDROUS	4	HBB
AZACITIDINE	4	HBB
AZATHIOPRINE	4	HBB
TOPOTECAN HYDROCHLORIDE	4	HBB
ACYCLOVIR	4	HBB
FLUOROURACIL	4	HBB
RAUWOLFIA SERPENTINA	4	HBB
HYDROQUINONE	4	HBB
MENADIONE	4	HBB
THIOTEPA	4	HBB
THIOGUANINE	4	HBB
RESERPINE	4	HBB
CURCUMIN	3	HBB
HYDROXYCAMPTOTHECIN	3	HBB
MOLIBRESIB	2	HBB
FISETIN	2	HBB
TEROXIRONE	2	HBB
5-FLUOROURIDINE	2	HBB
ELLAGIC ACID	2	HBB
BAICALEIN	2	HBB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HBB	68	Binding:50, Functional:18

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

23 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)
CANDESARTAN CILEXETIL	4	HBB
MECHLORETHAMINE HYDROCHLORIDE	4	HBB
PHENAZOPYRIDINE HYDROCHLORIDE	4	HBB
MERCAPTOPURINE ANHYDROUS	4	HBB
AZACITIDINE	4	HBB
AZATHIOPRINE	4	HBB
TOPOTECAN HYDROCHLORIDE	4	HBB
ACYCLOVIR	4	HBB
FLUOROURACIL	4	HBB
RAUWOLFIA SERPENTINA	4	HBB
HYDROQUINONE	4	HBB
MENADIONE	4	HBB
THIOTEPA	4	HBB
THIOGUANINE	4	HBB
RESERPINE	4	HBB
CURCUMIN	3	HBB
HYDROXYCAMPTOTHECIN	3	HBB
MOLIBRESIB	2	HBB
FISETIN	2	HBB
TEROXIRONE	2	HBB
5-FLUOROURIDINE	2	HBB
ELLAGIC ACID	2	HBB
BAICALEIN	2	HBB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HBB
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 28.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	14
PHASE1/PHASE2	4
PHASE2/PHASE3	3
PHASE4	2
PHASE2	2
PHASE3	1
EARLY_PHASE1	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00171301	PHASE4	COMPLETED	Extension Study of the Efficacy and Safety of Deferasirox Treatment in Beta-thalassemia Patients With Transfusional Hemosiderosis (Study Amended to 2-year Duration)
NCT02342145	PHASE4	COMPLETED	Efficacy of Basiliximab in the Prevention of Acute Graft-versus-host Disease in Unrelated Allogeneic Hematopoietic Stem Cell Transplantation Therapy for Thalassemia Major
NCT00999349	PHASE2/PHASE3	UNKNOWN	Therapeutic Effects of Silymarin in Patients With B-thalassemia Major
NCT01511848	PHASE2/PHASE3	UNKNOWN	Study Of Efficacy,Safety of Combined Deferasirox and Deferiprone Versus Combined Deferiprone and Desferal In Conditions of Iron Overload
NCT02173951	PHASE2/PHASE3	UNKNOWN	An Algorithm to Start Iron Chelation in Minimally Transfused Young Beta-thalassemia Major Patients
NCT04353986	PHASE3	UNKNOWN	PK of SOF/LED in HCV - Infected Adolescents With Haematological Disorders
NCT03653338	PHASE1/PHASE2	RECRUITING	T-Cell Depleted Alternative Donor Bone Marrow Transplant for Sickle Cell Disease (SCD) and Other Anemias
NCT01571635	PHASE2	TERMINATED	Study to Determine the Safety and Tolerability of Sotatercept (ACE-011) in Adults With Beta( β)- Thalassemia.
NCT02151526	PHASE1/PHASE2	COMPLETED	A Study Evaluating the Safety and Efficacy of LentiGlobin BB305 Drug Product in β-Thalassemia Major (Also Referred to as Transfusion-dependent β-Thalassemia [TDT]) and Sickle Cell Disease
NCT02435901	PHASE1/PHASE2	COMPLETED	HSCT For Patients With High Risk Hemoglobinopathies Using Reduced Intensity
NCT03276455	PHASE1/PHASE2	UNKNOWN	Gene Therapy for Beta-Thalassemia Major Using Autologous Hematopoietic Stem Cell Genetically Modified
NCT04092205	PHASE2	COMPLETED	Phase 2a Pilot Study of NBMI Treatment in Patients With Beta Thalassemia Major, Requiring Iron Chelation
NCT06291961	PHASE1	COMPLETED	A Safety and Efficacy Study Evaluating CS-101 in Subjects With β-Thalassemia Major
NCT04776850	EARLY_PHASE1	WITHDRAWN	Pre-transplant Immunosuppression and Donor Stem Cell Transplant for the Treatment of Severe Hemoglobinopathies
NCT06466304	Not specified	RECRUITING	Inspiratory Muscle Training in Children With Beta Thalasemia
NCT06980662	Not specified	NOT_YET_RECRUITING	The Effect of Laughter Yoga in Beta Thalassaemia Major Patients: a Randomised Controlled Trial
NCT00658385	Not specified	COMPLETED	Assess the Feasibility and Safety of Granulocyte Colony Stimulating Factor (GCSF) Mobilization of CD34+ Hematopoietic Progenitor Cells in Patients With Betathalassemia Major
NCT02198508	Not specified	COMPLETED	Clinical Trial of Deferasirox Combination Treatment With Deferiprone In Thalassaemia Patients
NCT02671695	Not specified	COMPLETED	Effect of Spirulina Compared to Amlodipine on Cardiac Iron Overload in Children With Beta Thalassemia
NCT02674607	Not specified	COMPLETED	the Potential Immunomodulatory Effects of Spirulina on Thalassemic Children
NCT02744105	Not specified	COMPLETED	Effect of Spirulina on Liver Fibrosis by Transient Elastography in Beta Thalassemic Children With Hepatitis C
NCT02744547	Not specified	COMPLETED	Effect of Spirulina on Serum Hyaluronic Acid in Beta Thalassemic Children With Hepatitis C
NCT02744560	Not specified	COMPLETED	Effect of Spirulina on Liver Iron Concentration in Beta Thalassemic Children With Hepatitis C
NCT03101423	Not specified	UNKNOWN	Monitoring of Chimerism After Transplantation in Patients With β Thalassemia Major and the Treatment Strategies for the Reduction of Chimerism
NCT03947632	Not specified	COMPLETED	Anthropometric Measurements in Children Having Transfusion-dependent Beta Thalassemia
NCT06831799	Not specified	COMPLETED	ERN-EuroBloodNet Registry on Patients With Rare Red Blood Cell Defects and COVID-19
NCT07153926	Not specified	COMPLETED	Elastography vs Iron Regulators in the Diagnosis of Hepatic Fibrosis- Iron Overload in Children With Beta- Thalassemia
NCT07486531	Not specified	COMPLETED	Iron Accumulation in Erythrocytes in Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MYCOPHENOLATE MOFETIL	4	3
DEFERASIROX	4	1
DEFERIPRONE	4	1
LEDIPASVIR	4	1
METHOTREXATE	4	1
SOFOSBUVIR	4	1
SOTATERCEPT	4	1
SILIBININ	3	1
SILYBIN A	3	1
EMERAMIDE	2	1
CHEMBL426	0	1
CHEMBL5308485	0	1
CHEMBL1258950	0	1
CHEMBL1259058	0	1
CHEMBL4634610	0	1
CHEMBL3621381	0	1
CHEMBL4455858	0	1
SILYBIN B	0	1
SILYMARIN	0	1
HEPCIDIN	-1	1