Hawkinsinuria

Summary

Hawkinsinuria (MONDO:0007700) is a disease caused by HPD (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HPD (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 370
• Phenotypes (HPO): 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001942	Metabolic acidosis	Very frequent (80-99%)
HP:0002213	Fine hair	Very frequent (80-99%)
HP:0003161	4-Hydroxyphenylpyruvic aciduria	Very frequent (80-99%)
HP:0003607	4-Hydroxyphenylacetic aciduria	Very frequent (80-99%)
HP:0008070	Sparse hair	Very frequent (80-99%)
HP:0010917	Abnormality of tyrosine metabolism	Very frequent (80-99%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0000821	Hypothyroidism	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hawkinsinuria
Mondo ID	MONDO:0007700
MeSH	C535845
OMIM	140350
Orphanet	2118
DOID	DOID:0111362
ICD-11	786595759
SNOMED CT	414380008
UMLS	C2931042
MedGen	419319
GARD	0005668
Is cancer (heuristic)	no

Also known as: 4-alpha-hydroxyphenylpyruvate hydroxylase deficiency · 4-HPPD deficiency · 4-hydroxyphenylpyruvic acid dioxygenase deficiency · hawkinsinuria

Data availability: 370 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 amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn disorder of phenylalanine and tyrosine metabolism › disorder of tyrosine metabolism › hawkinsinuria

Related subtypes (4): tyrosinemia, alkaptonuria, TH-deficient dopa-responsive dystonia, oculocutaneous albinism type 1

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

370 retrieved; paginated sample, class counts are floors:

236 likely benign, 64 uncertain significance, 28 pathogenic, 12 conflicting classifications of pathogenicity, 11 benign, 9 likely pathogenic, 6 benign/likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2110723	NM_002150.3(HPD):c.184dup (p.Ile62fs)	HPD	Pathogenic	criteria provided, single submitter
2128171	NM_002150.3(HPD):c.91C>T (p.Gln31Ter)	HPD	Pathogenic	criteria provided, single submitter
2153024	NM_002150.3(HPD):c.613C>T (p.Gln205Ter)	HPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2429187	NM_002150.3(HPD):c.248del (p.Gly83fs)	HPD	Pathogenic	criteria provided, multiple submitters, no conflicts
2921754	NM_002150.3(HPD):c.715_724del (p.Pro239fs)	HPD	Pathogenic	criteria provided, single submitter
2922293	NM_002150.3(HPD):c.852_853dup (p.Gly285fs)	HPD	Pathogenic	criteria provided, single submitter
2932690	NM_002150.3(HPD):c.850_853del (p.Arg284fs)	HPD	Pathogenic	criteria provided, single submitter
2946803	NM_002150.3(HPD):c.146del (p.Gly49fs)	HPD	Pathogenic	criteria provided, single submitter
2948128	NM_002150.3(HPD):c.865_866del (p.Leu289fs)	HPD	Pathogenic	criteria provided, single submitter
2950625	NM_002150.3(HPD):c.142del (p.Arg48fs)	HPD	Pathogenic	criteria provided, single submitter
3244248	NC_000012.11:g.(?122284748)(122296729_?)del	HPD	Pathogenic	criteria provided, single submitter
3244249	NC_000012.11:g.(?122296573)(122296729_?)del	HPD	Pathogenic	criteria provided, single submitter
3244250	NC_000012.11:g.(?122294469)(122296729_?)del	HPD	Pathogenic	criteria provided, single submitter
3244251	NC_000012.11:g.(?122292589)(122296729_?)del	HPD	Pathogenic	criteria provided, single submitter
3244252	NC_000012.11:g.(?122277634)(122287716_?)del	HPD	Pathogenic	criteria provided, single submitter
3244253	NC_000012.11:g.(?122286885)(122287716_?)del	HPD	Pathogenic	criteria provided, single submitter
3244254	NC_000012.11:g.(?122284839)(122288809_?)del	HPD	Pathogenic	criteria provided, single submitter
3574324	NM_002150.3(HPD):c.673C>T (p.Arg225Ter)	HPD	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3753445	NM_002150.3(HPD):c.274G>T (p.Gly92Ter)	HPD	Pathogenic	criteria provided, single submitter
3753543	NM_002150.3(HPD):c.65_66del (p.Val22fs)	HPD	Pathogenic	criteria provided, single submitter
3754946	NM_002150.3(HPD):c.535del (p.Glu179fs)	HPD	Pathogenic	criteria provided, single submitter
529472	NC_000012.12:g.(?121843690)(121847234_?)del	HPD	Pathogenic	criteria provided, single submitter
642856	NM_002150.3(HPD):c.158dup (p.Ser54fs)	HPD	Pathogenic	criteria provided, single submitter
832353	NC_000012.12:g.(?121846842)(121849810_?)del	HPD	Pathogenic	criteria provided, single submitter
953791	NM_002150.3(HPD):c.852_853del (p.Gly285fs)	HPD	Pathogenic	criteria provided, single submitter
979166	NM_002150.3(HPD):c.722A>G (p.Asn241Ser)	HPD	Pathogenic	no assertion criteria provided
1405283	NM_002150.3(HPD):c.204_205del (p.Phe69fs)	LOC126861662	Pathogenic	criteria provided, single submitter
2939489	NM_002150.3(HPD):c.250_253dup (p.His85fs)	LOC126861662	Pathogenic	criteria provided, single submitter
2952980	NM_002150.3(HPD):c.256del (p.Leu86fs)	LOC126861662	Pathogenic	criteria provided, single submitter
2949601	NM_002150.3(HPD):c.148del (p.Leu50fs)	TIALD	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
HPD	Strong	Autosomal dominant	hawkinsinuria	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HPD	Orphanet:2118	Hawkinsinuria
HPD	Orphanet:69723	Tyrosinemia type 3

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
HPD	HGNC:5147	ENSG00000158104	P32754	4-hydroxyphenylpyruvate dioxygenase	gencc,clinvar
TIALD	HGNC:56938	ENSG00000256811		transcript inducer of AURKA lysosomal degradation	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HPD	4-hydroxyphenylpyruvate dioxygenase	Catalyzes the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, one of the steps in tyrosine catabolism.

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)
HPD	Enzyme (other)	yes	1.13.11.27	Glyas_Fos-R_dOase_dom, 4OHPhenylPyrv_dOase, Glyas_Bleomycin-R_OHBP_Dase
TIALD	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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	2
right lobe of liver	2
adult mammalian kidney	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HPD	163	broad	marker	right lobe of liver, liver, adult mammalian kidney
TIALD	97		yes	right lobe of liver, liver, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HPD	1,766
TIALD	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HPD	P32754	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Tyrosine catabolism	1	2284.0×	4e-04	HPD

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
L-tyrosine catabolic process	1	2808.7×	5e-04	HPD
L-phenylalanine catabolic process	1	2106.5×	5e-04	HPD

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
HPD	NITISINONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HPD	1	4
TIALD	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NITISINONE	4	HPD

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HPD	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HPD	1.13.11.27	4-hydroxyphenylpyruvate dioxygenase

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

1 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)
NITISINONE	4	HPD

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HPD
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	TIALD

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)
TIALD	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.