Hypoxanthine guanine phosphoribosyltransferase partial deficiency

Summary

Hypoxanthine guanine phosphoribosyltransferase partial deficiency (MONDO:0010299) is a disease caused by HPRT1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: HPRT1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 185
• Phenotypes (HPO): 18

Clinical features

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000112	Nephropathy	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0002149	Hyperuricemia	Frequent (30-79%)
HP:0003149	Hyperuricosuria	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000707	Abnormality of the nervous system	Occasional (5-29%)
HP:0000791	Uric acid nephrolithiasis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001919	Acute kidney injury	Occasional (5-29%)
HP:0001997	Gout	Occasional (5-29%)
HP:0002071	Abnormality of extrapyramidal motor function	Occasional (5-29%)
HP:0003259	Elevated circulating creatinine concentration	Occasional (5-29%)
HP:0012587	Macroscopic hematuria	Occasional (5-29%)
HP:0100518	Dysuria	Occasional (5-29%)
HP:0000742	Self-mutilation	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypoxanthine guanine phosphoribosyltransferase partial deficiency
Mondo ID	MONDO:0010299
MeSH	C562583
OMIM	300323
Orphanet	79233
DOID	DOID:0112127
SNOMED CT	238007004
UMLS	C0268117
MedGen	82770
GARD	0016710
Is cancer (heuristic)	no

Also known as: HPRT deficiency, grade I · HPRT partial deficiency · HPRT-related gout · HPRT-related hyperuricemia · HPRT1 partial deficiency · hyperuricemia, HRPT-related, X-linked recessive · hypoxanthine guanine phosphoribosyltransferase 1 partial deficiency · hypoxanthine guanine phosphoribosyltransferase deficiency, grade I · Kelley-Seegmiller syndrome

Data availability: 185 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of purine or pyrimidine metabolism › inborn disorder of purine metabolism › hypoxanthine-guanine phosphoribosyltransferase deficiency › hypoxanthine guanine phosphoribosyltransferase partial deficiency

Related subtypes (1): Lesch-Nyhan syndrome

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

185 retrieved; paginated sample, class counts are floors:

64 likely benign, 43 pathogenic, 36 uncertain significance, 13 likely pathogenic, 12 benign, 8 pathogenic; other, 4 benign/likely benign, 4 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
10029	NM_000194.2(HPRT1):c.396T>G (p.Ile132Met)	HPRT1	Pathogenic; other	no assertion criteria provided
10031	NM_000194.2(HPRT1):c.602A>G (p.Asp201Gly)	HPRT1	Pathogenic; other	no assertion criteria provided
10042	NM_000194.2(HPRT1):c.312C>A (p.Ser104Arg)	HPRT1	Pathogenic; other	no assertion criteria provided
10044	NM_000194.2(HPRT1):c.209G>A (p.Gly70Glu)	HPRT1	Pathogenic	criteria provided, single submitter
10046	NM_000194.3(HPRT1):c.325C>T (p.Gln109Ter)	HPRT1	Pathogenic	criteria provided, multiple submitters, no conflicts
10059	NM_000194.2(HPRT1):c.151C>G (p.Arg51Gly)	HPRT1	Pathogenic; other	no assertion criteria provided
10060	NM_000194.2(HPRT1):c.151C>T (p.Arg51Ter)	HPRT1	Pathogenic	criteria provided, multiple submitters, no conflicts
10063	NM_000194.3(HPRT1):c.508C>T (p.Arg170Ter)	HPRT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10073	NM_000194.2(HPRT1):c.503C>T (p.Thr168Ile)	HPRT1	Pathogenic	no assertion criteria provided
10074	NM_000194.2(HPRT1):c.46G>A (p.Gly16Ser)	HPRT1	Pathogenic; other	no assertion criteria provided
10075	NM_000194.2(HPRT1):c.172G>A (p.Gly58Arg)	HPRT1	Pathogenic; other	no assertion criteria provided
10076	NM_000194.2(HPRT1):c.232C>G (p.Leu78Val)	HPRT1	Pathogenic; other	no assertion criteria provided
10077	HPRT CHERMSIDE	HPRT1	Pathogenic	criteria provided, single submitter
10081	NM_000194.2(HPRT1):c.582C>G (p.Asp194Glu)	HPRT1	Pathogenic; other	no assertion criteria provided
10084	NM_000194.3(HPRT1):c.193C>T (p.Leu65Phe)	HPRT1	Pathogenic	no assertion criteria provided
1039442	NM_000194.3(HPRT1):c.486-3C>G	HPRT1	Pathogenic	criteria provided, single submitter
1074315	NM_000194.3(HPRT1):c.212G>T (p.Gly71Val)	HPRT1	Pathogenic	criteria provided, single submitter
1076613	NC_000023.10:g.(?132670132)(133634127_?)del	HPRT1	Pathogenic	criteria provided, single submitter
1390125	NM_000194.3(HPRT1):c.118G>T (p.Gly40Ter)	HPRT1	Pathogenic	criteria provided, single submitter
1452349	NM_000194.3(HPRT1):c.472dup (p.Val158fs)	HPRT1	Pathogenic	criteria provided, single submitter
1454295	NM_000194.3(HPRT1):c.11_17del (p.Arg4fs)	HPRT1	Pathogenic	criteria provided, single submitter
1456809	NM_000194.3(HPRT1):c.556_557del (p.Lys186fs)	HPRT1	Pathogenic	criteria provided, single submitter
1459930	NM_000194.3(HPRT1):c.430C>T (p.Gln144Ter)	HPRT1	Pathogenic	criteria provided, single submitter
1460213	NC_000023.10:g.(?133632400)(133634107_?)del	HPRT1	Pathogenic	criteria provided, single submitter
1512051	NM_000194.3(HPRT1):c.191C>A (p.Ala64Asp)	HPRT1	Pathogenic	criteria provided, single submitter
167181	NM_000194.3(HPRT1):c.212dup (p.Tyr72fs)	HPRT1	Pathogenic	criteria provided, multiple submitters, no conflicts
2138720	NM_000194.3(HPRT1):c.212del (p.Gly71fs)	HPRT1	Pathogenic	criteria provided, single submitter
2138722	NM_000194.3(HPRT1):c.289_290del (p.Val97fs)	HPRT1	Pathogenic	criteria provided, multiple submitters, no conflicts
2138723	NM_000194.3(HPRT1):c.333_334del (p.Asp113fs)	HPRT1	Pathogenic	criteria provided, single submitter
2138724	NM_000194.3(HPRT1):c.611A>T (p.His204Leu)	HPRT1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
HPRT1	Strong	X-linked	hypoxanthine guanine phosphoribosyltransferase partial deficiency	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HPRT1	Orphanet:510	Lesch-Nyhan syndrome
HPRT1	Orphanet:79233	Hypoxanthine guanine phosphoribosyltransferase partial deficiency

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HPRT1	HGNC:5157	ENSG00000165704	P00492	Hypoxanthine-guanine phosphoribosyltransferase	gencc,clinvar
MIR106A	HGNC:31494	ENSG00000284157		microRNA 106a	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HPRT1	Hypoxanthine-guanine phosphoribosyltransferase	Converts guanine to guanosine monophosphate, and hypoxanthine to inosine monophosphate.

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HPRT1	Enzyme (other)	yes	2.4.2.8	PRTase_dom, Hxn_phspho_trans, PRTase-like
MIR106A	Other/Unknown	no

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	1

Top tissues across cohort

Tissue	Cohort genes
middle temporal gyrus	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HPRT1	298	ubiquitous	marker	oocyte, secondary oocyte, middle temporal gyrus
MIR106A			yes

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HPRT1	5,848
MIR106A	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HPRT1	P00492	24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Defective HPRT1 disrupts guanine and hypoxanthine salvage	1	11420.0×	3e-04	HPRT1
Purine salvage	1	878.5×	0.002	HPRT1
Azathioprine ADME	1	496.5×	0.002	HPRT1

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
guanine salvage	1	16852.0×	5e-04	HPRT1
adenine metabolic process	1	16852.0×	5e-04	HPRT1
hypoxanthine metabolic process	1	16852.0×	5e-04	HPRT1
hypoxanthine salvage	1	8426.0×	7e-04	HPRT1
GMP catabolic process	1	5617.3×	8e-04	HPRT1
positive regulation of dopamine metabolic process	1	4213.0×	8e-04	HPRT1
IMP metabolic process	1	4213.0×	8e-04	HPRT1
IMP salvage	1	3370.4×	8e-04	HPRT1
GMP salvage	1	2808.7×	8e-04	HPRT1
AMP salvage	1	2808.7×	8e-04	HPRT1
purine ribonucleoside salvage	1	2407.4×	8e-04	HPRT1
lymphocyte proliferation	1	2407.4×	8e-04	HPRT1
purine nucleotide biosynthetic process	1	1296.3×	0.001	HPRT1
cerebral cortex neuron differentiation	1	1203.7×	0.001	HPRT1
T cell mediated cytotoxicity	1	1123.5×	0.001	HPRT1
grooming behavior	1	1123.5×	0.001	HPRT1
striatum development	1	1123.5×	0.001	HPRT1
dopamine metabolic process	1	991.3×	0.001	HPRT1
central nervous system neuron development	1	802.5×	0.002	HPRT1
dopaminergic neuron differentiation	1	624.1×	0.002	HPRT1
response to amphetamine	1	495.6×	0.002	HPRT1
dendrite morphogenesis	1	432.1×	0.003	HPRT1
protein homotetramerization	1	237.3×	0.004	HPRT1
locomotory behavior	1	179.3×	0.006	HPRT1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HPRT1	0	0
MIR106A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HPRT1	67	Binding:52, Functional:12, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HPRT1	2.4.2.8	hypoxanthine phosphoribosyltransferase

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	HPRT1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MIR106A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HPRT1	67	—
MIR106A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.