AMED syndrome, digenic

Summary

AMED syndrome, digenic (MONDO:0030894) is a disease caused by ADH5 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ADH5 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	AMED syndrome, digenic
Mondo ID	MONDO:0030894
OMIM	619151
Orphanet	611216
DOID	DOID:0080952
UMLS	C5436906
MedGen	1754257
GARD	0018026
Is cancer (heuristic)	no

Also known as: AMeD syndrome · AMED syndrome, digenic · AMEDS · aplastic anemia-intellectual disability-dwarfism syndrome · bone marrow failure syndrome 7, digenic

Data availability: 6 ClinVar variants · 2 GenCC gene-disease records · 9 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › bone marrow disorder › bone marrow failure syndrome › AMED syndrome, digenic

Related subtypes (7): autosomal dominant aplasia and myelodysplasia, pancytopenia-developmental delay syndrome, bone marrow failure syndrome 3, bone marrow failure syndrome 4, bone marrow failure syndrome 6, bone marrow failure syndrome 5, Ziegler-Huang syndrome

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

6 retrieved; paginated sample, class counts are floors:

4 pathogenic, 1 drug response, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
4277919	NM_000671.4(ADH5):c.114+1G>A	ADH5	Pathogenic	criteria provided, single submitter
995825	NM_000671.4(ADH5):c.966del (p.Gly321_Trp322insTer)	ADH5	Pathogenic	criteria provided, single submitter
995826	NM_000671.4(ADH5):c.564+1G>A	ADH5	Pathogenic	no assertion criteria provided
995827	NM_000671.4(ADH5):c.832G>C (p.Ala278Pro)	ADH5	Pathogenic	criteria provided, single submitter
18390	NM_000690.4(ALDH2):c.1510G>A (p.Glu504Lys)	ALDH2	drug response	reviewed by expert panel
3065836	NM_000671.4(ADH5):c.938_943del (p.Thr313_Trp314del)	ADH5	Uncertain significance	criteria provided, single submitter

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
ADH5	Strong	Autosomal recessive	AMED syndrome, digenic	2

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
ADH5	HGNC:253	ENSG00000197894	P11766	Alcohol dehydrogenase class-3	gencc,clinvar
ALDH2	HGNC:404	ENSG00000111275	P05091	Aldehyde dehydrogenase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADH5	Alcohol dehydrogenase class-3	Catalyzes the oxidation of long-chain primary alcohols and the oxidation of S-(hydroxymethyl) glutathione.
ALDH2	Aldehyde dehydrogenase, mitochondrial	Required for clearance of cellular formaldehyde, a cytotoxic and carcinogenic metabolite that induces DNA damage.

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)
ADH5	Other/Unknown	no		ADH_Zn_CS, GroES-like_sf, ADH-like_C
ALDH2	Enzyme (other)	yes	1.2.1.3	Aldehyde_DH_dom, Ald_DH_CS_CYS, Ald_DH/histidinol_DH

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
descending thoracic aorta	1
mucosa of stomach	1
stromal cell of endometrium	1
liver	1
lower lobe of lung	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADH5	302	ubiquitous	marker	mucosa of stomach, descending thoracic aorta, stromal cell of endometrium
ALDH2	301	ubiquitous	marker	right lobe of liver, liver, lower lobe of lung

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH2	4,554
ADH5	2,126

Intra-cohort edges

A	B	Sources
ADH5	ALDH2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDH2	P05091	29
ADH5	P11766	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Ethanol oxidation	2	951.7×	1e-05	ADH5, ALDH2
Phase I - Functionalization of compounds	2	219.6×	1e-04	ADH5, ALDH2
Biological oxidations	2	129.8×	3e-04	ADH5, ALDH2
Metabolism of serotonin	1	2855.0×	0.001	ALDH2
Serotonin clearance from the synaptic cleft	1	1427.5×	0.002	ALDH2
Neurotransmitter clearance	1	634.4×	0.003	ALDH2
Smooth Muscle Contraction	1	132.8×	0.012	ALDH2
Metabolism	2	11.6×	0.012	ADH5, ALDH2
Mitochondrial protein degradation	1	57.1×	0.025	ALDH2
Muscle contraction	1	38.6×	0.031	ALDH2
Transmission across Chemical Synapses	1	38.1×	0.031	ALDH2
Neuronal System	1	22.1×	0.048	ALDH2
Metabolism of proteins	1	6.2×	0.155	ALDH2

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
nitroglycerin metabolic process	1	8426.0×	7e-04	ALDH2
regulation of dopamine biosynthetic process	1	8426.0×	7e-04	ALDH2
regulation of serotonin biosynthetic process	1	8426.0×	7e-04	ALDH2
ethanol metabolic process	1	4213.0×	0.001	ALDH2
aldehyde catabolic process	1	2808.7×	0.001	ALDH2
formaldehyde catabolic process	1	2808.7×	0.001	ADH5
response to nitrosative stress	1	2106.5×	0.001	ADH5
fatty acid omega-oxidation	1	1404.3×	0.002	ADH5
alcohol metabolic process	1	1203.7×	0.002	ALDH2
cellular detoxification of aldehyde	1	1053.2×	0.002	ALDH2
response to redox state	1	648.1×	0.002	ADH5
ethanol catabolic process	1	601.9×	0.002	ALDH2
positive regulation of blood pressure	1	526.6×	0.002	ADH5
respiratory system process	1	468.1×	0.003	ADH5
retinoid metabolic process	1	247.8×	0.005	ADH5
carbohydrate metabolic process	1	68.0×	0.016	ALDH2
response to lipopolysaccharide	1	62.4×	0.016	ADH5

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

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
ALDH2	DISULFIRAM

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALDH2	3	4
ADH5	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DISULFIRAM	4	ALDH2
N6022	3	ADH5
THIRAM	2	ALDH2
DAIDZEIN	2	ALDH2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ALDH2	71	Binding:66, Functional:5
ADH5	19	Binding:19

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDH2	1.2.1.3	aldehyde dehydrogenase (NAD+)

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

4 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)
DISULFIRAM	4	ALDH2
N6022	3	ADH5
THIRAM	2	ALDH2
DAIDZEIN	2	ALDH2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ALDH2
B	Phased (≥1) drug, not yet approved	1	ADH5
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.