3-hydroxyacyl-CoA dehydrogenase deficiency

Summary

3-hydroxyacyl-CoA dehydrogenase deficiency (MONDO:0017715) is a disease caused by HADH (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: HADH (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 291
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	3-hydroxyacyl-CoA dehydrogenase deficiency
Mondo ID	MONDO:0017715
MeSH	C535310
OMIM	231530
Orphanet	309127
UMLS	C1291230
MedGen	266222
GARD	0021319
Is cancer (heuristic)	no

Data availability: 291 ClinVar variants · 2 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 energy metabolism › disorder of fatty acid and ketone body metabolism › disorder of fatty acid oxidation and ketogenesis › 3-hydroxyacyl-CoA dehydrogenase deficiency

Related subtypes (9): very long chain acyl-CoA dehydrogenase deficiency, carnitine-acylcarnitine translocase deficiency, systemic primary carnitine deficiency disease, 3-hydroxy-3-methylglutaric aciduria, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, acyl-CoA dehydrogenase 9 deficiency, acyl-CoA dehydrogenase deficiency, long chain acyl-CoA dehydrogenase 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

ClinVar germline variants

291 retrieved; paginated sample, class counts are floors:

143 likely benign, 47 uncertain significance, 45 conflicting classifications of pathogenicity, 13 likely pathogenic, 12 benign/likely benign, 12 pathogenic, 11 uncertain significance/uncertain risk allele, 3 benign, 3 pathogenic/likely pathogenic, 1 likely risk allele, 1 pathogenic/likely pathogenic/likely risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
2440673	NM_005327.7(HADH):c.203dup (p.Ile70fs)	HADH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675961	NM_005327.7(HADH):c.419+1G>A	HADH	Pathogenic	criteria provided, single submitter
2726575	NM_005327.7(HADH):c.516del (p.Phe172fs)	HADH	Pathogenic	criteria provided, single submitter
2758232	NM_005327.7(HADH):c.304_307dup (p.Ser103fs)	HADH	Pathogenic	criteria provided, single submitter
2796951	NM_005327.7(HADH):c.493C>T (p.Arg165Ter)	HADH	Pathogenic	criteria provided, single submitter
2809363	NM_005327.7(HADH):c.664_668del (p.Leu222fs)	HADH	Pathogenic	criteria provided, single submitter
2826330	NM_005327.7(HADH):c.369del (p.Asn123_Leu124insTer)	HADH	Pathogenic	criteria provided, single submitter
2836479	NM_005327.7(HADH):c.64del (p.Ala22fs)	HADH	Pathogenic	criteria provided, single submitter
3246655	NC_000004.11:g.(?108911089)(108955513_?)del	HADH	Pathogenic	criteria provided, single submitter
3246656	NC_000004.11:g.(?108911089)(108911240_?)del	HADH	Pathogenic	criteria provided, single submitter
3645395	NM_005327.7(HADH):c.776_779del (p.Phe259fs)	HADH	Pathogenic	criteria provided, single submitter
3674169	NM_005327.7(HADH):c.859del (p.His287fs)	HADH	Pathogenic	criteria provided, single submitter
3678133	NM_005327.7(HADH):c.854del (p.Pro285fs)	HADH	Pathogenic	criteria provided, single submitter
39482	NM_005327.7(HADH):c.706C>T (p.Arg236Ter)	HADH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802082	NM_005327.7(HADH):c.261+1G>A	HADH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802083	NM_005327.7(HADH):c.587del (p.Ser196fs)	HADH	Pathogenic/Likely pathogenic/Likely risk allele	criteria provided, multiple submitters, no conflicts
1685343	NM_005327.7(HADH):c.636+2_636+3insCT	HADH	Likely pathogenic	criteria provided, single submitter
2446434	NM_005327.7(HADH):c.166_169del (p.Val56fs)	HADH	Likely pathogenic	criteria provided, single submitter
2675956	NM_005327.7(HADH):c.262-2A>G	HADH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675957	NM_005327.7(HADH):c.424dup (p.Thr142fs)	HADH	Likely pathogenic	criteria provided, single submitter
2675958	NM_005327.7(HADH):c.130C>T (p.Gln44Ter)	HADH	Likely pathogenic	criteria provided, single submitter
2675959	NM_005327.7(HADH):c.419+1G>C	HADH	Likely pathogenic	criteria provided, single submitter
2675960	NM_005327.7(HADH):c.709+2T>C	HADH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2707419	NM_005327.7(HADH):c.636+2T>C	HADH	Likely pathogenic	criteria provided, single submitter
2874131	NM_005327.7(HADH):c.261+2T>A	HADH	Likely pathogenic	criteria provided, single submitter
3241723	NM_005327.7(HADH):c.710-1G>A	HADH	Likely pathogenic	criteria provided, single submitter
3241724	NM_005327.7(HADH):c.271G>T (p.Glu91Ter)	HADH	Likely pathogenic	criteria provided, single submitter
3589733	NM_005327.7(HADH):c.132+1G>A	HADH	Likely pathogenic	criteria provided, single submitter
659541	NM_005327.7(HADH):c.100G>C (p.Gly34Arg)	HADH	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1007414	NM_005327.7(HADH):c.740C>T (p.Ala247Val)	HADH	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
HADH	Definitive	Autosomal recessive	hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HADH	Orphanet:71212	Hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency
CYP2U1	Orphanet:320411	Autosomal recessive spastic paraplegia type 56

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
HADH	HGNC:4799	ENSG00000138796	Q16836	Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial	gencc,clinvar
CYP2U1	HGNC:20582	ENSG00000155016	Q7Z449	Cytochrome P450 2U1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HADH	Hydroxyacyl-coenzyme A dehydrogenase, mitochondrial	Mitochondrial fatty acid beta-oxidation enzyme that catalyzes the third step of the beta-oxidation cycle for medium and short-chain 3-hydroxy fatty acyl-CoAs (C4 to C10).
CYP2U1	Cytochrome P450 2U1	A cytochrome P450 monooxygenase involved in the metabolism of arachidonic acid and its conjugates.

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)
HADH	Enzyme (other)	yes	1.1.1.35	3HC_DH_C, 3-OHacyl-CoA_DH_NAD-bd, 3-OHacyl-CoA_DH_CS
CYP2U1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_E_grp-I_CYP2D-like

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
heart right ventricle	1
islet of Langerhans	1
skeletal muscle tissue of rectus abdominis	1
epithelial cell of pancreas	1
germinal epithelium of ovary	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HADH	296	ubiquitous	marker	islet of Langerhans, heart right ventricle, skeletal muscle tissue of rectus abdominis
CYP2U1	241	ubiquitous	marker	thymus, germinal epithelium of ovary, epithelial cell of pancreas

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HADH	2,386
CYP2U1	1,748

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HADH	Q16836	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP2U1	Q7Z449	88.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CYP2U1 causes SPG56	1	5710.0×	0.002	CYP2U1
Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA	1	1142.0×	0.002	HADH
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	1	1142.0×	0.002	HADH
Beta oxidation of hexanoyl-CoA to butanoyl-CoA	1	1142.0×	0.002	HADH
Beta oxidation of butanoyl-CoA to acetyl-CoA	1	1142.0×	0.002	HADH
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	1	951.7×	0.002	HADH
Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)	1	634.4×	0.002	CYP2U1
Miscellaneous substrates	1	475.8×	0.002	CYP2U1
Mitochondrial protein degradation	1	57.1×	0.017	HADH

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
cytochrome metabolic process	1	1685.2×	0.006	CYP2U1
obsolete organic acid metabolic process	1	1203.7×	0.006	CYP2U1
omega-hydroxylase P450 pathway	1	766.0×	0.006	CYP2U1
negative regulation of insulin secretion	1	247.8×	0.011	HADH
regulation of insulin secretion	1	195.9×	0.011	HADH
fatty acid beta-oxidation	1	187.2×	0.011	HADH
steroid metabolic process	1	168.5×	0.011	CYP2U1
response to activity	1	162.0×	0.011	HADH
response to insulin	1	115.4×	0.013	HADH
positive regulation of cold-induced thermogenesis	1	81.8×	0.017	HADH
xenobiotic metabolic process	1	74.6×	0.017	CYP2U1
response to xenobiotic stimulus	1	34.5×	0.034	HADH
spermatogenesis	1	17.6×	0.060	HADH
cell differentiation	1	14.6×	0.068	HADH

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
CYP2U1	PAZOPANIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP2U1	1	4
HADH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PAZOPANIB	4	CYP2U1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CYP2U1	183	ADMET:181, Binding:2
HADH	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HADH	1.1.1.35	3-hydroxyacyl-CoA dehydrogenase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CYP2U1	183

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

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)
PAZOPANIB	4	CYP2U1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYP2U1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	HADH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
HADH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns