Hereditary persistence of fetal hemoglobin

Summary

Hereditary persistence of fetal hemoglobin (MONDO:0020989) is a disease caused by HBB (GenCC Strong), with 4 cohort genes. The dominant Reactome pathway is Factors involved in megakaryocyte development and platelet production (3 cohort genes).

At a glance

• Causal gene: HBB (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 137

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary persistence of fetal hemoglobin
Mondo ID	MONDO:0020989
ICD-10-CM	D56.4
NCIT	C129072
SNOMED CT	191201002
UMLS	C0019025
MedGen	5495
GARD	0025271
Is cancer (heuristic)	no

Also known as: Disease, Haemoglobin F · Disease, Hemoglobin F · Haemoglobin F Disease · Hb F disease · HEMOGLOBIN F DIS · Hemoglobin F Disease · hereditary persistence of fetal hemoglobin · Hereditary Persistence of Foetal Haemoglobin · Hereditary persistence of foetal haemoglobin · HPFH - Hereditary persistence of fetal hemoglobin · HPFH - Hereditary persistence of foetal haemoglobin

Data availability: 137 ClinVar variants · 1 GenCC gene-disease record · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inherited hemoglobinopathy › hereditary persistence of fetal hemoglobin

Related subtypes (16): thalassemia, congenital nonspherocytic hemolytic anemia, sulfhemoglobinemia, congenital, sickle cell disease, hemoglobin C disease, hemoglobin E disease, sickle cell-beta-thalassemia disease syndrome, sickle cell-hemoglobin d disease syndrome, sickle cell-hemoglobin E disease syndrome, hereditary persistence of fetal hemoglobin-sickle cell disease syndrome, beta-thalassemia and related diseases, hemoglobinopathy Toms River, hereditary methemoglobinemia, hemoglobin D disease, unstable hemoglobin disease, homozygous hemoglobin O Arab disease

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

137 retrieved; paginated sample, class counts are floors:

53 pathogenic, 24 uncertain significance, 23 pathogenic/likely pathogenic, 17 conflicting classifications of pathogenicity, 8 benign, 5 likely benign, 5 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
15126	NM_000518.4(HBB):c.19G>A (p.Glu7Lys)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15152	NM_000518.4(HBB):c.364G>C (p.Glu122Gln)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15161	NM_000518.5(HBB):c.79G>A (p.Glu27Lys)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15234	NM_000518.4(HBB):c.92G>C (p.Arg31Thr)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15239	NM_000518.5(HBB):c.82G>T (p.Ala28Ser)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15292	NM_000518.4(HBB):c.364G>A (p.Glu122Lys)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15300	NM_000518.5(HBB):c.61G>A (p.Val21Met)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15333	NM_000518.5(HBB):c.20A>T (p.Glu7Val)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15401	NM_000518.5(HBB):c.52A>T (p.Lys18Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15402	NM_000518.5(HBB):c.118C>T (p.Gln40Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15407	NM_000518.5(HBB):c.184A>T (p.Lys62Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15408	NM_000518.5(HBB):c.108C>A (p.Tyr36Ter)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15413	NM_000518.5(HBB):c.25_26del (p.Lys9fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15414	NM_000518.5(HBB):c.51del (p.Lys18fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15415	NM_000518.5(HBB):c.135del (p.Phe46fs)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15417	NM_000518.5(HBB):c.126_129del (p.Phe42fs)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15418	NM_000518.5(HBB):c.20del (p.Glu7fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15419	NM_000518.5(HBB):c.217dup (p.Ser73fs)	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
15422	NM_000518.5(HBB):c.17_18del (p.Pro6fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15426	NM_000518.5(HBB):c.45dup (p.Trp16fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15431	NM_000518.5(HBB):c.112del (p.Trp38fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15432	NM_000518.5(HBB):c.85dup (p.Leu29fs)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15434	NM_000518.5(HBB):c.2T>G (p.Met1Arg)	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15436	NM_000518.5(HBB):c.92+1G>A	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15438	NM_000518.5(HBB):c.315+1G>A	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15446	NM_000518.5(HBB):c.93-1G>A	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
15448	NM_000518.5(HBB):c.92+5G>T	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15449	NM_000518.5(HBB):c.92+5G>A	HBB	Pathogenic	criteria provided, multiple submitters, no conflicts
15450	NM_000518.5(HBB):c.92+6T>C	HBB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 33 · Orphanet: 36 · 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	Strong	Autosomal dominant	hereditary persistence of fetal hemoglobin	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
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
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

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HBB	HGNC:4827	ENSG00000244734	P68871	Hemoglobin subunit beta	gencc,clinvar
ACSBG1	HGNC:29567	ENSG00000103740	Q96GR2	Long-chain-fatty-acid–CoA ligase ACSBG1	clinvar
HBG1	HGNC:4831	ENSG00000213934	P69891	Hemoglobin subunit gamma-1	clinvar
HBG2	HGNC:4832	ENSG00000196565	P69892	Hemoglobin subunit gamma-2	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.
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.
HBG2	Hemoglobin subunit gamma-2	Gamma chains make up the fetal hemoglobin F, in combination with alpha chains.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HBB	Other/Unknown	no		Globin, Hemoglobin_b, Globin-like_sf
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
HBG2	Other/Unknown	no		Globin, Hemoglobin_b, Globin-like_sf

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
placenta	2
monocyte	1
trabecular bone tissue	1
vena cava	1
C1 segment of cervical spinal cord	1
inferior olivary complex	1
upper leg skin	1
blood	1
male germ line stem cell (sensu Vertebrata) in testis	1
adrenal tissue	1
ganglionic eminence	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
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
HBG2	129	tissue_specific	marker	placenta, adrenal tissue, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACSBG1	1,697
HBB	454
HBG2	66
HBG1	33

Intra-cohort edges

A	B	Sources
HBG1	HBG2	intact

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HBB	P68871	350
HBG2	P69892	4
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 4 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	HBB, HBG1, 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 4 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	972.2×	3e-08	HBB, HBG1, HBG2
oxygen transport	3	789.9×	3e-08	HBB, HBG1, HBG2
erythrocyte development	3	395.0×	2e-07	HBB, HBG1, HBG2
nitric oxide transport	1	842.6×	0.006	HBB
cellular oxidant detoxification	1	468.1×	0.008	HBB
renal absorption	1	421.3×	0.008	HBB
long-chain fatty-acyl-CoA biosynthetic process	1	210.7×	0.011	ACSBG1
very long-chain fatty acid metabolic process	1	191.5×	0.011	ACSBG1
hydrogen peroxide catabolic process	1	168.5×	0.011	HBB
long-chain fatty acid metabolic process	1	156.0×	0.011	ACSBG1
blood vessel diameter maintenance	1	156.0×	0.011	HBB
response to hydrogen peroxide	1	117.0×	0.012	HBB
positive regulation of nitric oxide biosynthetic process	1	113.9×	0.012	HBB
long-chain fatty acid biosynthetic process	1	110.9×	0.012	ACSBG1
platelet aggregation	1	84.3×	0.015	HBB
response to glucocorticoid	1	81.0×	0.015	ACSBG1
myelination	1	62.9×	0.018	ACSBG1
regulation of blood pressure	1	55.4×	0.019	HBB
inflammatory response	1	9.4×	0.102	HBB

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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

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
HBG1	1	Binding:1
HBG2	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	3	ACSBG1, HBG1, HBG2

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)
ACSBG1	0	—
HBG1	1	—
HBG2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.