Hao-Fountain syndrome

Summary

Hao-Fountain syndrome (MONDO:0014805) is a disease caused by USP7 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: USP7 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 43

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		18	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Hao-Fountain syndrome
Mondo ID	MONDO:0014805
Orphanet	643549
UMLS	C5393908
MedGen	1719035
GARD	0025017
NORD	1917
Is cancer (heuristic)	no

Also known as: HAFOUS · USP7-Related Diseases

Data availability: 43 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › Hao-Fountain syndrome

Related subtypes (20): intellectual disability, microcephaly, Williams syndrome, Aicardi syndrome, toluene embryopathy, alternating hemiplegia, atypical Rett syndrome, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, complex neurodevelopmental disorder, Mendelian neurodevelopmental disorder, TCF7L2-related neurodevelopmental disorder, neurodevelopmental disorder with seizures and brain abnormalities, Yoon-Bellen neurodevelopmental syndrome, neurodevelopmental disorder with microcephaly, hypotonia, and absent language, neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss, neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, neurodevelopmental disorder with parkinsonism or other movement abnormalities, neurodevelopmental disorder with seizures and impaired intellectual and language development, Ebstein-Bezieau neurodevelopmental syndrome, Luo-Agrawal neurodevelopmental syndrome

Subtypes (2): Hao-Fountain syndrome due to 16p13.2 microdeletion, Hao-Fountain syndrome due to USP7 mutation

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

43 retrieved; paginated sample, class counts are floors:

18 likely pathogenic, 14 uncertain significance, 9 pathogenic, 1 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2500242	NC_000016.9:g.(?8160554)(9074348_?)del	CARHSP1	Pathogenic	no assertion criteria provided
1172595	NM_003470.3(USP7):c.2596C>T (p.Gln866Ter)	USP7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1713161	NM_003470.3(USP7):c.247_250del (p.Glu83fs)	USP7	Pathogenic	no assertion criteria provided
1805368	NM_003470.3(USP7):c.701dup (p.Thr235fs)	USP7	Pathogenic	criteria provided, single submitter
224721	NM_003470.3(USP7):c.429C>G (p.Tyr143Ter)	USP7	Pathogenic	no assertion criteria provided
2683752	NM_003470.3(USP7):c.1722del (p.Gln574fs)	USP7	Pathogenic	no assertion criteria provided
440942	NM_003470.3(USP7):c.675G>A (p.Met225Ile)	USP7	Pathogenic	no assertion criteria provided
4537329	NC_000016.9:g.(9024255_9057063)(9057764?)del	USP7	Pathogenic	criteria provided, single submitter
917892	NM_003470.3(USP7):c.1728T>A (p.Cys576Ter)	USP7	Pathogenic	no assertion criteria provided
917895	NM_003470.3(USP7):c.3202+1G>T	USP7	Pathogenic	no assertion criteria provided
1068189	NM_003470.3(USP7):c.352T>C (p.Phe118Leu)	USP7	Likely pathogenic	criteria provided, single submitter
1164067	NM_003470.3(USP7):c.1175G>C (p.Gly392Ala)	USP7	Likely pathogenic	no assertion criteria provided
1299454	NM_003470.3(USP7):c.1033G>A (p.Glu345Lys)	USP7	Likely pathogenic	criteria provided, single submitter
1320052	NM_003470.3(USP7):c.862_863del (p.Leu288fs)	USP7	Likely pathogenic	criteria provided, single submitter
1526154	NM_003470.3(USP7):c.1157T>A (p.Leu386Ter)	USP7	Likely pathogenic	criteria provided, single submitter
1713170	NM_003470.3(USP7):c.992A>G (p.Tyr331Cys)	USP7	Likely pathogenic	no assertion criteria provided
1713185	NM_003470.3(USP7):c.835T>G (p.Leu279Val)	USP7	Likely pathogenic	no assertion criteria provided
2412746	NM_003470.3(USP7):c.1849_1850dup (p.Gln617fs)	USP7	Likely pathogenic	criteria provided, single submitter
2500240	NM_003470.3(USP7):c.1297C>A (p.Leu433Ile)	USP7	Likely pathogenic	no assertion criteria provided
2500241	NM_003470.3(USP7):c.713T>G (p.Leu238Arg)	USP7	Likely pathogenic	no assertion criteria provided
2500244	NM_003470.3(USP7):c.1258A>G (p.Lys420Glu)	USP7	Likely pathogenic	no assertion criteria provided
2500245	NM_003470.3(USP7):c.884A>G (p.Asp295Gly)	USP7	Likely pathogenic	no assertion criteria provided
2500246	NM_003470.3(USP7):c.721-1G>C	USP7	Likely pathogenic	no assertion criteria provided
2500247	NM_003470.3(USP7):c.2132_2140+9del	USP7	Likely pathogenic	no assertion criteria provided
2500248	NM_003470.3(USP7):c.2232_2235del (p.Arg745fs)	USP7	Likely pathogenic	no assertion criteria provided
2572973	NM_003470.3(USP7):c.1754A>T (p.Asp585Val)	USP7	Likely pathogenic	no assertion criteria provided
2572974	NM_003470.3(USP7):c.1691A>C (p.Tyr564Ser)	USP7	Likely pathogenic	no assertion criteria provided
522827	NM_003470.3(USP7):c.2169_2170del (p.Arg723fs)	USP7	Likely pathogenic	criteria provided, single submitter
1342501	NM_003470.3(USP7):c.2785G>A (p.Val929Met)	USP7	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679716	NM_003470.3(USP7):c.2140C>T (p.Arg714Cys)	USP7	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
USP7	Definitive	Autosomal dominant	Hao-Fountain syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
USP7	Orphanet:500055	Hao-Fountain syndrome due to 16p13.2 microdeletion
USP7	Orphanet:643538	Hao-Fountain syndrome due to USP7 mutation

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
USP7	HGNC:12630	ENSG00000187555	Q93009	Ubiquitin carboxyl-terminal hydrolase 7	gencc,clinvar
CARHSP1	HGNC:17150	ENSG00000153048	Q9Y2V2	Calcium-regulated heat-stable protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
USP7	Ubiquitin carboxyl-terminal hydrolase 7	Hydrolase that deubiquitinates target proteins such as ARMC5, FOXO4, DEPTOR, KAT5, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and DAXX.
CARHSP1	Calcium-regulated heat-stable protein 1	Binds mRNA and regulates the stability of target mRNA.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Protease	1	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USP7	Protease	yes		Peptidase_C19_UCH, MATH/TRAF_dom, TRAF-like
CARHSP1	Other/Unknown	no		CSP_DNA-bd, CSD, NA-bd_OB-fold

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
calcaneal tendon	1
middle temporal gyrus	1
ganglionic eminence	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
USP7	294	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, calcaneal tendon
CARHSP1	282	ubiquitous	marker	right testis, left testis, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
USP7	5,896
CARHSP1	1,875

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
USP7	Q93009	84
CARHSP1	Q9Y2V2	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 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
Regulation of PTEN localization	1	1038.2×	0.007	USP7
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	1	368.4×	0.007	USP7
Regulation of TP53 Degradation	1	292.8×	0.007	USP7
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1	265.6×	0.007	USP7
Formation of TC-NER Pre-Incision Complex	1	211.5×	0.007	USP7
Gap-filling DNA repair synthesis and ligation in TC-NER	1	178.4×	0.007	USP7
Dual incision in TC-NER	1	173.0×	0.007	USP7
Ub-specific processing proteases	1	53.1×	0.019	USP7

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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 telomere capping	1	8426.0×	0.003	USP7
regulation of establishment of protein localization to telomere	1	2808.7×	0.003	USP7
symbiont-mediated disruption of host cell PML body	1	2808.7×	0.003	USP7
regulation of retrograde transport, endosome to Golgi	1	2106.5×	0.003	USP7
monoubiquitinated protein deubiquitination	1	936.2×	0.004	USP7
DNA alkylation repair	1	766.0×	0.004	USP7
obsolete regulation of DNA-binding transcription factor activity	1	766.0×	0.004	USP7
transcription-coupled nucleotide-excision repair	1	601.9×	0.005	USP7
negative regulation of gene expression via chromosomal CpG island methylation	1	526.6×	0.005	USP7
negative regulation of gluconeogenesis	1	401.2×	0.005	USP7
regulation of mRNA stability	1	210.7×	0.009	CARHSP1
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	200.6×	0.009	USP7
regulation of signal transduction by p53 class mediator	1	191.5×	0.009	USP7
negative regulation of TORC1 signaling	1	162.0×	0.010	USP7
regulation of circadian rhythm	1	129.6×	0.011	USP7
rhythmic process	1	125.8×	0.011	USP7
protein deubiquitination	1	88.7×	0.015	USP7
regulation of protein stability	1	62.9×	0.019	USP7
protein stabilization	1	33.4×	0.034	USP7
protein ubiquitination	1	20.7×	0.052	USP7
intracellular signal transduction	1	19.1×	0.054	CARHSP1
proteolysis	1	17.1×	0.058	USP7

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
USP7	ASTEMIZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
USP7	5	4
CARHSP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ASTEMIZOLE	4	USP7
SERTRALINE	4	USP7
BARDOXOLONE METHYL	3	USP7
MOLIBRESIB	2	USP7
URSOLIC ACID	2	USP7

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
USP7	268	Binding:264, Functional:4
CARHSP1	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
USP7	268

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

5 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)
ASTEMIZOLE	4	USP7
SERTRALINE	4	USP7
BARDOXOLONE METHYL	3	USP7
MOLIBRESIB	2	USP7
URSOLIC ACID	2	USP7

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	USP7
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	CARHSP1

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)
CARHSP1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.