acyl-CoA dehydrogenase 9 deficiency

Summary

acyl-CoA dehydrogenase 9 deficiency (MONDO:0012624) is a disease caused by ACAD9 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: ACAD9 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 316
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		23	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0011923	Decreased activity of mitochondrial complex I	Obligate (100%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001298	Encephalopathy	Frequent (30-79%)
HP:0001397	Hepatic steatosis	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001635	Congestive heart failure	Frequent (30-79%)
HP:0001639	Hypertrophic cardiomyopathy	Frequent (30-79%)
HP:0001644	Dilated cardiomyopathy	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0001987	Hyperammonemia	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Frequent (30-79%)
HP:0003128	Lactic acidosis	Frequent (30-79%)
HP:0003198	Myopathy	Frequent (30-79%)
HP:0003234	Decreased circulating carnitine concentration	Frequent (30-79%)
HP:0003324	Generalized muscle weakness	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003473	Fatigable weakness	Frequent (30-79%)
HP:0008151	Prolonged prothrombin time	Frequent (30-79%)
HP:0008331	Elevated creatine kinase after exercise	Frequent (30-79%)
HP:0025435	Increased circulating lactate dehydrogenase concentration	Frequent (30-79%)
HP:0045045	Elevated plasma acylcarnitine levels	Frequent (30-79%)
HP:0001645	Sudden cardiac death	Occasional (5-29%)
HP:0001958	Nonketotic hypoglycemia	Occasional (5-29%)
HP:0002181	Cerebral edema	Occasional (5-29%)
HP:0003215	Dicarboxylic aciduria	Occasional (5-29%)
HP:0006554	Acute hepatic failure	Occasional (5-29%)
HP:0011695	Cerebellar hemorrhage	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acyl-CoA dehydrogenase 9 deficiency
Mondo ID	MONDO:0012624
MeSH	C567006
OMIM	611126
Orphanet	99901
DOID	DOID:0112072
SNOMED CT	725046003
UMLS	C4747517
MedGen	1648400
GARD	0012986
Is cancer (heuristic)	no

Also known as: ACAD9 deficiency · acyl-CoA dehydrogenase 9 deficiency · mitochondrial complex I deficiency due to ACAD9 deficiency · mitochondrial complex I deficiency, nuclear type 20

Data availability: 316 ClinVar variants · 5 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 › acyl-CoA dehydrogenase 9 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 deficiency, 3-hydroxyacyl-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

316 retrieved; paginated sample, class counts are floors:

99 uncertain significance, 80 likely pathogenic, 40 conflicting classifications of pathogenicity, 39 pathogenic/likely pathogenic, 19 likely benign, 18 benign, 14 pathogenic, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
424744	NM_014049.4(ACAD9):c.[1030-1G>T];[1249C>T]		Pathogenic	no assertion criteria provided
424745	NM_014049.4(ACAD9):c.[1015T>G];[2T>G]		Pathogenic	no assertion criteria provided
424746	NM_014049.4(ACAD9):c.[1594C>T];[359delT]		Pathogenic	no assertion criteria provided
424747	NM_014049.4(ACAD9):c.[1595G>A];[976G>A]		Pathogenic	no assertion criteria provided
424748	NM_014049.4(ACAD9):c.[1298G>A];[151-2A>G]		Pathogenic	no assertion criteria provided
424749	NM_014049.4(ACAD9):c.[1237G>A];[1552C>T]		Pathogenic	no assertion criteria provided
424750	NM_014049.4(ACAD9):c.[1552C>T];[1564-6_1569del]		Pathogenic	no assertion criteria provided
424751	NM_014049.4(ACAD9):c.[1A>G];[796C>T]		Pathogenic	no assertion criteria provided
1031232	NM_014049.5(ACAD9):c.1278+1G>A	ACAD9	Pathogenic	criteria provided, single submitter
1033254	NM_014049.5(ACAD9):c.184dup (p.Asp62fs)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070934	NM_014049.5(ACAD9):c.1462G>T (p.Gly488Ter)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074141	NM_014049.5(ACAD9):c.970dup (p.Glu324fs)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074449	NM_014049.5(ACAD9):c.1060dup (p.Tyr354fs)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075114	NM_014049.5(ACAD9):c.253C>T (p.Arg85Ter)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1253828	NM_014049.5(ACAD9):c.1168G>A (p.Ala390Thr)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1352447	NM_014049.5(ACAD9):c.497_501del (p.Tyr165_Leu166insTer)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1394209	NM_014049.5(ACAD9):c.825del (p.Phe275fs)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1407949	NM_014049.5(ACAD9):c.205C>T (p.Gln69Ter)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1415957	NM_014049.5(ACAD9):c.340G>T (p.Glu114Ter)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1430768	NM_014049.5(ACAD9):c.1288_1291dup (p.Ile431fs)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1439431	NM_014049.5(ACAD9):c.1A>T (p.Met1Leu)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451120	NM_014049.5(ACAD9):c.1240C>A (p.Arg414Ser)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453047	NM_014049.4(ACAD9):c.153_156del	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456169	NM_014049.5(ACAD9):c.957del (p.Ile319fs)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456248	NM_014049.5(ACAD9):c.187G>T (p.Glu63Ter)	ACAD9	Pathogenic	criteria provided, multiple submitters, no conflicts
1952491	NM_014049.5(ACAD9):c.517del (p.Glu173fs)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1988383	NM_014049.5(ACAD9):c.1806_1816dup (p.Leu606fs)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2182872	NM_014049.5(ACAD9):c.1385_1386del (p.Thr462fs)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242461	NM_014049.5(ACAD9):c.1552C>T (p.Arg518Cys)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242463	NM_014049.5(ACAD9):c.1237G>A (p.Glu413Lys)	ACAD9	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
ACAD9	Definitive	Autosomal recessive	acyl-CoA dehydrogenase 9 deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACAD9	Orphanet:99901	Acyl-CoA dehydrogenase 9 deficiency

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
ACAD9	HGNC:21497	ENSG00000177646	Q9H845	Complex I assembly factor ACAD9, mitochondrial	gencc,clinvar
CFAP92	HGNC:29231	ENSG00000114656	Q9ULG3	Uncharacterized protein CFAP92	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACAD9	Complex I assembly factor ACAD9, mitochondrial	Together with NDUFAF1 and ECSIT, forms part of the mitochondrial complex I (MCIA),which is required for the biogenesis of respiratory Complex I (CI) and is therefore crucial for the activation of the oxidative phosphorylation system.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACAD9	Other/Unknown	no		Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C
CFAP92	Other/Unknown	no		DUF4550

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
left ventricle myocardium	1
skin of abdomen	1
upper arm skin	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACAD9	258	ubiquitous	marker	upper arm skin, skin of abdomen, left ventricle myocardium
CFAP92	170	broad	marker	left testis, right testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACAD9	3,600
CFAP92	1,397

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACAD9	Q9H845	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CFAP92	Q9ULG3	57.39

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Complex I biogenesis	1	165.5×	0.015	ACAD9
Respiratory electron transport	1	95.2×	0.015	ACAD9
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	ACAD9
Metabolism	1	11.6×	0.086	ACAD9

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
medium-chain fatty acid metabolic process	1	2808.7×	0.001	ACAD9
long-chain fatty acid metabolic process	1	624.1×	0.002	ACAD9
mitochondrial respiratory chain complex I assembly	1	411.0×	0.002	ACAD9

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
ACAD9	0	0
CFAP92	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
ACAD9	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ACAD9, CFAP92

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)
ACAD9	1	—
CFAP92	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.