Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

Summary

Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome (MONDO:0018749) is a disease caused by variants in HBG1 and HBG2, with 6 cohort genes. The dominant Reactome pathway is Factors involved in megakaryocyte development and platelet production (3 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Causal genes: HBG1 (GenCC Strong), HBG2 (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 4
• Phenotypes (HPO): 6

Clinical features

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0000980	Pallor	Very frequent (80-99%)
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0011904	Persistence of hemoglobin F	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0003330	Abnormal bone structure	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
Mondo ID	MONDO:0018749
Orphanet	46532
ICD-11	418601307
UMLS	C0271994
MedGen	543715
GARD	0018642
Is cancer (heuristic)	no

Also known as: HPFH-beta-thalassemia syndrome

Data availability: 4 ClinVar variants · 6 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › beta-thalassemia and related diseases › hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

Related subtypes (6): beta-thalassemia-X-linked thrombocytopenia syndrome, delta-beta-thalassemia, hemoglobin C-beta-thalassemia syndrome, hemoglobin E-beta-thalassemia syndrome, hemoglobin Lepore-beta-thalassemia syndrome, beta thalassemia

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

4 retrieved; paginated sample, class counts are floors:

2 uncertain risk allele, 1 uncertain significance, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4083487	NM_015898.4(ZBTB7A):c.722C>T (p.Pro241Leu)	ZBTB7A	Uncertain risk allele	no assertion criteria provided
4083489	NM_015898.4(ZBTB7A):c.830AGG[2] (p.Glu279del)	ZBTB7A	Uncertain risk allele	no assertion criteria provided
1048099	NM_000559.3(HBG1):c.-29G>A	HBG1	Uncertain significance	criteria provided, single submitter
4083488	NM_015898.4(ZBTB7A):c.1032C>T (p.Asp344=)	ZBTB7A	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 55 · Orphanet: 40 · 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
ACSBG1	Strong	Autosomal dominant	hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome	4
HBG1	Strong	Autosomal dominant	hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome	4
HBG2	Strong	Autosomal dominant	hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome	6
KLF1	Supportive	Autosomal recessive	hereditary persistence of fetal hemoglobin-sickle cell disease syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HBG1	Orphanet:231237	Delta-beta-thalassemia
HBG1	Orphanet:251380	Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
HBG1	Orphanet:46532	Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
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
HBG2	Orphanet:251380	Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
HBG2	Orphanet:280615	Low oxygen affinity gamma chain hemoglobin disease
HBG2	Orphanet:46532	Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
HBG2	Orphanet:707792	Unstable gamma globin chain variant disease
KLF1	Orphanet:251380	Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
KLF1	Orphanet:293825	Congenital dyserythropoietic anemia type IV
KLF1	Orphanet:46532	Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
ZBTB7A	Orphanet:694956	Intellectual disability-lymphoid hypertrophy-macrocephaly syndrome

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
ACSBG1	HGNC:29567	ENSG00000103740	Q96GR2	Long-chain-fatty-acid–CoA ligase ACSBG1	gencc,clinvar
HBG1	HGNC:4831	ENSG00000213934	P69891	Hemoglobin subunit gamma-1	gencc,clinvar
HBB	HGNC:4827	ENSG00000244734	P68871	Hemoglobin subunit beta	gencc
HBG2	HGNC:4832	ENSG00000196565	P69892	Hemoglobin subunit gamma-2	gencc
KLF1	HGNC:6345	ENSG00000105610	Q13351	Krueppel-like factor 1	gencc
ZBTB7A	HGNC:18078	ENSG00000178951	O95365	Zinc finger and BTB domain-containing protein 7A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACSBG1	Long-chain-fatty-acid–CoA ligase ACSBG1	Catalyzes the conversion of fatty acids such as long-chain and very long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation.
HBG1	Hemoglobin subunit gamma-1	Gamma chains make up the fetal hemoglobin F, in combination with alpha chains.
HBB	Hemoglobin subunit beta	Involved in oxygen transport from the lung to the various peripheral tissues.
HBG2	Hemoglobin subunit gamma-2	Gamma chains make up the fetal hemoglobin F, in combination with alpha chains.
KLF1	Krueppel-like factor 1	Transcription regulator of erythrocyte development that probably serves as a general switch factor during erythropoiesis.
ZBTB7A	Zinc finger and BTB domain-containing protein 7A	Transcription factor that represses the transcription of a wide range of genes involved in cell proliferation and differentiation.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 4 · 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
Transcription factor	2	2.8×	0.316
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACSBG1	Other/Unknown	no		AMP-dep_synth/lig_dom, AMP-binding_CS, ANL_N_sf
HBG1	Other/Unknown	no		Globin, Hemoglobin_b, Globin-like_sf
HBB	Other/Unknown	no		Globin, Hemoglobin_b, Globin-like_sf
HBG2	Other/Unknown	no		Globin, Hemoglobin_b, Globin-like_sf
KLF1	Transcription factor	no		Znf_C2H2_type, EKLF_TAD2, EKLF_TAD1
ZBTB7A	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type

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
blood	2
placenta	2
trabecular bone tissue	2
C1 segment of cervical spinal cord	1
inferior olivary complex	1
upper leg skin	1
male germ line stem cell (sensu Vertebrata) in testis	1
monocyte	1
vena cava	1
adrenal tissue	1
ganglionic eminence	1
bone marrow	1
buccal mucosa cell	1
nipple	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACSBG1	207	broad	marker	upper leg skin, inferior olivary complex, C1 segment of cervical spinal cord
HBG1	121	tissue_specific	marker	placenta, blood, male germ line stem cell (sensu Vertebrata) in testis
HBB	284	broad	marker	monocyte, trabecular bone tissue, vena cava
HBG2	129	tissue_specific	marker	placenta, adrenal tissue, ganglionic eminence
KLF1	86	tissue_specific	marker	trabecular bone tissue, bone marrow, blood
ZBTB7A	281	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, nipple

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZBTB7A	1,737
ACSBG1	1,697
KLF1	1,682
HBB	454
HBG2	66
HBG1	33

Intra-cohort edges

A	B	Sources
HBG1	HBG2	intact

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HBB	P68871	350
ZBTB7A	O95365	11
HBG2	P69892	4
KLF1	Q13351	3
HBG1	P69891	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACSBG1	Q96GR2	84.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Factors involved in megakaryocyte development and platelet production	3	49.8×	2e-04	HBG1, HBB, HBG2
Heme assimilation	1	951.7×	0.008	HBB
Erythrocytes take up oxygen and release carbon dioxide	1	317.2×	0.014	HBB
Erythrocytes take up carbon dioxide and release oxygen	1	219.6×	0.014	HBB
Scavenging of heme from plasma	1	219.6×	0.014	HBB
Chaperone Mediated Autophagy	1	124.1×	0.017	HBB
Synthesis of very long-chain fatty acyl-CoAs	1	114.2×	0.017	ACSBG1
Fatty acyl-CoA biosynthesis	1	109.8×	0.017	ACSBG1
Late endosomal microautophagy	1	81.6×	0.020	HBB
Heme signaling	1	53.9×	0.028	HBB
Cytoprotection by HMOX1	1	46.0×	0.029	HBB
Fatty acid metabolism	1	32.8×	0.038	ACSBG1
Metabolism of lipids	1	7.9×	0.140	ACSBG1
Neutrophil degranulation	1	5.8×	0.174	HBB
Metabolism	1	2.9×	0.302	ACSBG1

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
carbon dioxide transport	3	648.1×	3e-07	HBG1, HBB, HBG2
oxygen transport	3	526.6×	3e-07	HBG1, HBB, HBG2
erythrocyte development	3	263.3×	2e-06	HBG1, HBB, HBG2
regulation of transcription regulatory region DNA binding	1	702.2×	0.016	ZBTB7A
nitric oxide transport	1	561.7×	0.016	HBB
cellular oxidant detoxification	1	312.1×	0.020	HBB
renal absorption	1	280.9×	0.020	HBB
double-strand break repair via classical nonhomologous end joining	1	280.9×	0.020	ZBTB7A
obsolete regulation of DNA-binding transcription factor activity	1	255.3×	0.020	ZBTB7A
cellular response to endothelin	1	234.1×	0.020	KLF1
regulation of glycolytic process	1	200.6×	0.021	ZBTB7A
maternal process involved in female pregnancy	1	156.0×	0.022	KLF1
negative regulation of androgen receptor signaling pathway	1	156.0×	0.022	ZBTB7A
long-chain fatty-acyl-CoA biosynthetic process	1	140.4×	0.022	ACSBG1
erythrocyte maturation	1	140.4×	0.022	ZBTB7A
very long-chain fatty acid metabolic process	1	127.7×	0.022	ACSBG1
hydrogen peroxide catabolic process	1	112.3×	0.023	HBB
long-chain fatty acid metabolic process	1	104.0×	0.023	ACSBG1
blood vessel diameter maintenance	1	104.0×	0.023	HBB
response to hydrogen peroxide	1	78.0×	0.028	HBB
positive regulation of nitric oxide biosynthetic process	1	75.9×	0.028	HBB
long-chain fatty acid biosynthetic process	1	73.9×	0.028	ACSBG1
negative regulation of Notch signaling pathway	1	72.0×	0.028	ZBTB7A
protein localization to nucleus	1	58.5×	0.033	ZBTB7A
platelet aggregation	1	56.2×	0.033	HBB
response to glucocorticoid	1	54.0×	0.033	ACSBG1
protein destabilization	1	48.4×	0.035	KLF1
erythrocyte differentiation	1	44.6×	0.037	KLF1
myelination	1	41.9×	0.037	ACSBG1
regulation of alternative mRNA splicing, via spliceosome	1	40.7×	0.037	ZBTB7A

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 5 of 6 evidence-associated genes (83%) 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
ACSBG1	0	0
HBG1	0	0
HBG2	0	0
KLF1	0	0
ZBTB7A	0	0

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
KLF1	4	Binding:4
ZBTB7A	2	Binding:2
HBG1	1	Binding:1
HBG2	1	Binding:1

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

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	5	ACSBG1, HBG1, HBG2, KLF1, ZBTB7A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACSBG1	0	—
HBG1	1	—
HBG2	1	—
KLF1	4	—
ZBTB7A	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.