Mitochondrial trifunctional protein deficiency 1

Summary

Mitochondrial trifunctional protein deficiency 1 (MONDO:0958181) is a disease caused by variants in HADHA and HADHB, with 3 cohort genes.

At a glance

• Causal genes: HADHA (GenCC Strong), HADHB (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 73

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial trifunctional protein deficiency 1
Mondo ID	MONDO:0958181
OMIM	609015
DOID	DOID:0070619
GARD	0026958
Is cancer (heuristic)	no

Data availability: 73 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 › inherited lipid metabolism disorder › mitochondrial trifunctional protein deficiency › mitochondrial trifunctional protein deficiency 1

Related subtypes (1): mitochondrial trifunctional protein deficiency 2

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

73 retrieved; paginated sample, class counts are floors:

32 pathogenic/likely pathogenic, 16 likely pathogenic, 13 conflicting classifications of pathogenicity, 6 pathogenic, 6 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
100085	NM_000182.5(HADHA):c.1528G>C (p.Glu510Gln)	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065948	NM_000182.5(HADHA):c.2026C>T (p.Arg676Cys)	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203745	NM_000182.5(HADHA):c.1916_1919dup (p.Glu641fs)	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2048816	NM_000182.5(HADHA):c.2020dup (p.Gln674fs)	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2503898	NM_000182.5(HADHA):c.1759_1760del (p.Leu587fs)	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3586242	NM_000182.5(HADHA):c.1091_1128del	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
558276	NM_000182.5(HADHA):c.1620+2_1620+6del	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
801655	NM_000182.5(HADHA):c.1689+2T>G	GAREM2	Pathogenic	criteria provided, multiple submitters, no conflicts
8732	NM_000182.5(HADHA):c.1678C>T (p.Arg560Ter)	GAREM2	Pathogenic	criteria provided, multiple submitters, no conflicts
1373566	NM_000182.5(HADHA):c.556C>T (p.Gln186Ter)	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188962	NM_000182.5(HADHA):c.1793_1794del (p.His598fs)	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188987	NM_000182.5(HADHA):c.703C>T (p.Arg235Trp)	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1910397	NM_000182.5(HADHA):c.761_764del (p.Lys254fs)	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
193564	NM_000182.5(HADHA):c.919-2A>G	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1979591	NM_000182.5(HADHA):c.2000+1G>A	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3586249	NM_000182.5(HADHA):c.68del	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
503510	NM_000182.5(HADHA):c.180_180+5delinsAT	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
552438	NM_000182.5(HADHA):c.72del (p.Gly23_Tyr24insTer)	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8730	NM_000182.5(HADHA):c.180+1G>A	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8731	NM_000182.5(HADHA):c.180+3A>G	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8736	NM_000182.5(HADHA):c.914T>A (p.Ile305Asn)	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8737	NM_000182.5(HADHA):c.871C>T (p.Arg291Ter)	HADHA	Pathogenic	criteria provided, multiple submitters, no conflicts
92594	NM_000182.5(HADHA):c.157C>T (p.Arg53Ter)	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
948895	NM_000182.5(HADHA):c.2027G>A (p.Arg676His)	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075534	NM_000183.3(HADHB):c.97C>T (p.Arg33Ter)	HADHB	Pathogenic	criteria provided, multiple submitters, no conflicts
14845	NM_000183.3(HADHB):c.182G>A (p.Arg61His)	HADHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14846	NM_000183.3(HADHB):c.740G>A (p.Arg247His)	HADHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1691100	NM_000183.3(HADHB):c.1165A>G (p.Asn389Asp)	HADHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1806798	NM_000183.3(HADHB):c.1137del (p.His379fs)	HADHB	Pathogenic	criteria provided, multiple submitters, no conflicts
2635256	NM_000183.3(HADHB):c.739C>T (p.Arg247Cys)	HADHB	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 4 · 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
HADHB	Definitive	Autosomal recessive	mitochondrial trifunctional protein deficiency	4
HADHA	Strong	Autosomal recessive	mitochondrial trifunctional protein deficiency	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HADHA	Orphanet:243367	Acute fatty liver of pregnancy
HADHA	Orphanet:5	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
HADHA	Orphanet:746	Mitochondrial trifunctional protein deficiency
HADHB	Orphanet:746	Mitochondrial trifunctional protein deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HADHA	HGNC:4801	ENSG00000084754	P40939	Trifunctional enzyme subunit alpha, mitochondrial	gencc,clinvar
HADHB	HGNC:4803	ENSG00000138029	P55084	Trifunctional enzyme subunit beta, mitochondrial	gencc,clinvar
GAREM2	HGNC:27172	ENSG00000157833	Q75VX8	GRB2-associated and regulator of MAPK protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HADHA	Trifunctional enzyme subunit alpha, mitochondrial	Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway.
HADHB	Trifunctional enzyme subunit beta, mitochondrial	Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway.
GAREM2	GRB2-associated and regulator of MAPK protein 2	Probable adapter protein that may provide a link between cell surface epidermal growth factor receptor and the MAPK/ERK signaling pathway.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HADHA	Enzyme (other)	yes	1.1.1.211	Enoyl-CoA_hydra/iso, 3HC_DH_C, 3-OHacyl-CoA_DH_NAD-bd
HADHB	Other/Unknown	no		Thiolase, Thiolase-like, Thiolase_AS
GAREM2	Other/Unknown	no		SAM/pointed_sf, CABIT_dom, GAREM

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
jejunal mucosa	1
muscle of leg	1
deltoid	1
heart right ventricle	1
left ventricle myocardium	1
caudate nucleus	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HADHA	295	ubiquitous	marker	jejunal mucosa, gastrocnemius, muscle of leg
HADHB	295	ubiquitous	marker	heart right ventricle, left ventricle myocardium, deltoid
GAREM2	187	ubiquitous	yes	ventricular zone, ganglionic eminence, caudate nucleus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HADHA	4,343
HADHB	4,047
GAREM2	667

Intra-cohort edges

A	B	Sources
HADHA	HADHB	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HADHA	P40939	3
HADHB	P55084	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GAREM2	Q75VX8	61.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 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
Beta oxidation of myristoyl-CoA to lauroyl-CoA	2	3806.7×	2e-07	HADHA, HADHB
Beta oxidation of palmitoyl-CoA to myristoyl-CoA	2	3806.7×	2e-07	HADHA, HADHB
Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA	2	2284.0×	2e-07	HADHA, HADHB
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	2	2284.0×	2e-07	HADHA, HADHB
Beta oxidation of hexanoyl-CoA to butanoyl-CoA	2	2284.0×	2e-07	HADHA, HADHB
Acyl chain remodeling of CL	2	1903.3×	2e-07	HADHA, HADHB
mitochondrial fatty acid beta-oxidation of unsaturated fatty acids	2	1903.3×	2e-07	HADHA, HADHB
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	2	1903.3×	2e-07	HADHA, HADHB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
fatty acid beta-oxidation	2	249.7×	2e-04	HADHA, HADHB
cardiolipin acyl-chain remodeling	1	1404.3×	0.003	HADHA
response to stress	1	802.5×	0.004	GAREM2
neuron projection extension	1	175.5×	0.013	GAREM2
cognition	1	95.2×	0.016	GAREM2
social behavior	1	90.6×	0.016	GAREM2
response to insulin	1	77.0×	0.017	HADHA
cellular response to lipopolysaccharide	1	32.7×	0.034	HADHB
gene expression	1	26.6×	0.037	HADHB

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HADHA	0	0
HADHB	0	0
GAREM2	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
HADHA	4	Binding:4
HADHB	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HADHA	1.1.1.211	long-chain-3-hydroxyacyl-CoA dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	HADHA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	HADHB, GAREM2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HADHA	4	—
HADHB	2	—
GAREM2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.