Hao-Fountain syndrome due to USP7 mutation

Summary

Hao-Fountain syndrome due to USP7 mutation (MONDO:0958071) is a disease caused by USP7 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: USP7 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 27

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Hao-Fountain syndrome due to USP7 mutation
Mondo ID	MONDO:0958071
OMIM	616863
Orphanet	643538
UMLS	C5816734
MedGen	1853151
GARD	0026917
Is cancer (heuristic)	no

Also known as: USP7-related neurodevelopmental disorder

Data availability: 27 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › Hao-Fountain syndrome › Hao-Fountain syndrome due to USP7 mutation

Related subtypes (1): Hao-Fountain syndrome due to 16p13.2 microdeletion

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

27 retrieved; paginated sample, class counts are floors:

18 uncertain significance, 4 pathogenic, 4 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3236128	NM_003470.3(USP7):c.3111+1G>A	USP7	Pathogenic	criteria provided, single submitter
3255088	NM_003470.3(USP7):c.1463del (p.Cys488fs)	USP7	Pathogenic	criteria provided, single submitter
4685497	NM_003470.3(USP7):c.786_787del (p.Arg262fs)	USP7	Pathogenic	criteria provided, single submitter
871804	NM_003470.3(USP7):c.1522C>T (p.Arg508Ter)	USP7	Pathogenic	criteria provided, multiple submitters, no conflicts
3237490	NM_003470.3(USP7):c.2403_2407del (p.Lys801fs)	USP7	Likely pathogenic	criteria provided, single submitter
4076295	NM_003470.3(USP7):c.2234_2235del (p.Arg745fs)	USP7	Likely pathogenic	criteria provided, single submitter
4530607	NM_003470.3(USP7):c.3067C>T (p.Arg1023Ter)	USP7	Likely pathogenic	criteria provided, single submitter
4820081	NM_003470.3(USP7):c.3040-1G>A	USP7	Likely pathogenic	criteria provided, single submitter
2438496	NM_003470.3(USP7):c.3163G>A (p.Glu1055Lys)	USP7	Uncertain significance	criteria provided, single submitter
3236348	NM_003470.3(USP7):c.2510T>G (p.Leu837Arg)	USP7	Uncertain significance	criteria provided, single submitter
3255089	NM_003470.3(USP7):c.698T>A (p.Phe233Tyr)	USP7	Uncertain significance	criteria provided, single submitter
3381173	NM_003470.3(USP7):c.1352A>G (p.His451Arg)	USP7	Uncertain significance	criteria provided, single submitter
3381234	NM_003470.3(USP7):c.229C>T (p.Arg77Cys)	USP7	Uncertain significance	criteria provided, single submitter
3382375	NM_003470.3(USP7):c.37_51dup (p.Leu17_Ser18insGlyGluGlnGlnLeu)	USP7	Uncertain significance	criteria provided, single submitter
3393127	NM_003470.3(USP7):c.1045G>T (p.Asp349Tyr)	USP7	Uncertain significance	criteria provided, single submitter
3775930	NM_003470.3(USP7):c.2951A>G (p.Lys984Arg)	USP7	Uncertain significance	criteria provided, single submitter
4076296	NM_003470.3(USP7):c.3202+6G>T	USP7	Uncertain significance	criteria provided, single submitter
4076297	NM_003470.3(USP7):c.771T>A (p.Pro257=)	USP7	Uncertain significance	criteria provided, single submitter
4292245	NM_003470.3(USP7):c.938G>A (p.Gly313Asp)	USP7	Uncertain significance	criteria provided, single submitter
4292647	NM_003470.3(USP7):c.1444G>A (p.Asp482Asn)	USP7	Uncertain significance	criteria provided, single submitter
4293667	NM_003470.3(USP7):c.1053G>C (p.Gln351His)	USP7	Uncertain significance	criteria provided, single submitter
4688151	NM_003470.3(USP7):c.2377C>T (p.Arg793Cys)	USP7	Uncertain significance	criteria provided, single submitter
4813454	NM_003470.3(USP7):c.511A>G (p.Met171Val)	USP7	Uncertain significance	criteria provided, single submitter
4818947	NM_003470.3(USP7):c.1271+4A>G	USP7	Uncertain significance	criteria provided, single submitter
4819790	NM_003470.3(USP7):c.2292CAT[1] (p.Ile766del)	USP7	Uncertain significance	criteria provided, single submitter
4846959	NM_003470.3(USP7):c.1755T>G (p.Asp585Glu)	USP7	Uncertain significance	criteria provided, single submitter
4814237	NM_003470.3(USP7):c.383C>T (p.Thr128Met)	USP7	Likely benign	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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
USP7	HGNC:12630	ENSG00000187555	Q93009	Ubiquitin carboxyl-terminal hydrolase 7	gencc,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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USP7	Protease	yes		Peptidase_C19_UCH, MATH/TRAF_dom, TRAF-like

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
Brodmann (1909) area 23	1
calcaneal tendon	1
middle temporal gyrus	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
USP7	5,896

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
USP7	Q93009	84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
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 1 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	16852.0×	0.001	USP7
regulation of establishment of protein localization to telomere	1	5617.3×	0.001	USP7
symbiont-mediated disruption of host cell PML body	1	5617.3×	0.001	USP7
regulation of retrograde transport, endosome to Golgi	1	4213.0×	0.001	USP7
monoubiquitinated protein deubiquitination	1	1872.4×	0.002	USP7
DNA alkylation repair	1	1532.0×	0.002	USP7
obsolete regulation of DNA-binding transcription factor activity	1	1532.0×	0.002	USP7
transcription-coupled nucleotide-excision repair	1	1203.7×	0.002	USP7
negative regulation of gene expression via chromosomal CpG island methylation	1	1053.2×	0.002	USP7
negative regulation of gluconeogenesis	1	802.5×	0.002	USP7
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	401.2×	0.004	USP7
regulation of signal transduction by p53 class mediator	1	383.0×	0.004	USP7
negative regulation of TORC1 signaling	1	324.1×	0.005	USP7
regulation of circadian rhythm	1	259.3×	0.005	USP7
rhythmic process	1	251.5×	0.005	USP7
protein deubiquitination	1	177.4×	0.007	USP7
regulation of protein stability	1	125.8×	0.009	USP7
protein stabilization	1	66.9×	0.017	USP7
protein ubiquitination	1	41.4×	0.025	USP7
proteolysis	1	34.2×	0.029	USP7

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
USP7	ASTEMIZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
USP7	5	4

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

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: 1; 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	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: 0.