3-hydroxyisobutyric aciduria

Summary

3-hydroxyisobutyric aciduria (MONDO:0009371) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		13	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0000044	Hypogonadotropic hypogonadism	Very frequent (80-99%)
HP:0003128	Lactic acidosis	Very frequent (80-99%)
HP:0000325	Triangular face	Frequent (30-79%)
HP:0000343	Long philtrum	Frequent (30-79%)
HP:0008551	Microtia	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000340	Sloping forehead	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001511	Intrauterine growth retardation	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002120	Cerebral cortical atrophy	Occasional (5-29%)
HP:0002514	Cerebral calcification	Occasional (5-29%)
HP:0007360	Aplasia/Hypoplasia of the cerebellum	Occasional (5-29%)
HP:0007370	Aplasia/Hypoplasia of the corpus callosum	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	3-hydroxyisobutyric aciduria
Mondo ID	MONDO:0009371
MeSH	C535312
OMIM	236795
Orphanet	939
ICD-11	1293648631
SNOMED CT	237957007
UMLS	C0342737
MedGen	90996
GARD	0005662
Is cancer (heuristic)	no

Also known as: 3-hydroxyisobutyric aciduria · disorder of valine metabolism

Data availability: 1 GenCC gene-disease record.

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 organic aciduria › classic organic aciduria › 3-hydroxyisobutyric aciduria

Related subtypes (14): beta-ketothiolase deficiency, isovaleric acidemia, 3-hydroxy-3-methylglutaric aciduria, 3-hydroxyisobutyryl-CoA hydrolase deficiency, methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, propionic acidemia, 2-methylbutyryl-CoA dehydrogenase deficiency, isobutyryl-CoA dehydrogenase deficiency, combined malonic and methylmalonic acidemia, multiple carboxylase deficiency, methylmalonic aciduria and homocystinuria, vitamin B12-responsive methylmalonic acidemia, 3-methylglutaconic aciduria, 3-methylcrotonyl-CoA carboxylase deficiency

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 0 · 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
HIBADH	Limited	Autosomal recessive	inborn organic aciduria	2

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
HIBADH	HGNC:4907	ENSG00000106049	P31937	3-hydroxyisobutyrate dehydrogenase, mitochondrial	gencc

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HIBADH	Other/Unknown	no		3-OH-isobutyrate_DH-rel_CS, 6PGDH_NADP-bd, 6-PGluconate_DH-like_C_sf

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
cardiac muscle of right atrium	1
kidney epithelium	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HIBADH	260	ubiquitous	marker	kidney epithelium, left ventricle myocardium, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HIBADH	2,364

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HIBADH	P31937	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Branched-chain amino acid catabolism	1	475.8×	0.006	HIBADH
Metabolism of amino acids and derivatives	1	67.6×	0.022	HIBADH
Metabolism	1	11.6×	0.086	HIBADH

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-valine catabolic process	1	3370.4×	3e-04	HIBADH

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HIBADH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HIBADH	2	Binding:2

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HIBADH

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)
HIBADH	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.