Diaphragmatic hernia 4, with cardiovascular defects

Summary

Diaphragmatic hernia 4, with cardiovascular defects (MONDO:0859571) is a disease caused by ALDH1A2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ALDH1A2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diaphragmatic hernia 4, with cardiovascular defects
Mondo ID	MONDO:0859571
OMIM	620025
UMLS	C5774210
MedGen	1823983
GARD	0026745
Is cancer (heuristic)	no

Data availability: 7 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › diaphragm disorder › congenital diaphragmatic hernia › diaphragmatic hernia 4, with cardiovascular defects

Related subtypes (4): diaphragmatic hernia 1, diaphragmatic hernia 2, hernia, anterior diaphragmatic, diaphragmatic hernia 3

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

7 retrieved; paginated sample, class counts are floors:

4 pathogenic, 3 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703736	NM_003888.4(ALDH1A2):c.544C>A (p.Gln182Lys)	ALDH1A2	Pathogenic	no assertion criteria provided
1703737	NM_003888.4(ALDH1A2):c.1382C>A (p.Ser461Tyr)	ALDH1A2	Pathogenic	no assertion criteria provided
1703738	NM_003888.4(ALDH1A2):c.1147G>A (p.Ala383Thr)	ALDH1A2	Pathogenic	no assertion criteria provided
1703739	NM_003888.4(ALDH1A2):c.1040G>A (p.Arg347His)	ALDH1A2	Pathogenic	no assertion criteria provided
3064766	NM_003888.4(ALDH1A2):c.117+7508dup	ALDH1A2	Uncertain significance	criteria provided, single submitter
3235240	NM_003888.4(ALDH1A2):c.1087-1G>T	ALDH1A2	Uncertain significance	criteria provided, single submitter
3235243	NM_003888.4(ALDH1A2):c.833G>A (p.Ser278Asn)	ALDH1A2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
ALDH1A2	Strong	Autosomal recessive	diaphragmatic hernia 4, with cardiovascular defects	3

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
ALDH1A2	HGNC:15472	ENSG00000128918	O94788	Retinal dehydrogenase 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALDH1A2	Retinal dehydrogenase 2	Catalyzes the NAD-dependent oxidation of aldehyde substrates, such as all-trans-retinal and all-trans-13,14-dihydroretinal, to their corresponding carboxylic acids, all-trans-retinoate and all-trans-13,14-dihydroretinoate, respectively.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALDH1A2	Enzyme (other)	yes	1.2.1.36	Aldehyde_DH_dom, Ald_DH_CS_CYS, Ald_DH/histidinol_DH

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
decidua	1
germinal epithelium of ovary	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALDH1A2	226	broad	marker	germinal epithelium of ovary, decidua, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALDH1A2	4,289

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALDH1A2	O94788	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
RA biosynthesis pathway	1	475.8×	0.005	ALDH1A2
Signaling by Retinoic Acid	1	407.9×	0.005	ALDH1A2
Signaling by Nuclear Receptors	1	102.0×	0.013	ALDH1A2
Signal Transduction	1	10.2×	0.098	ALDH1A2

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
determination of bilateral symmetry	1	16852.0×	0.002	ALDH1A2
regulation of vascular endothelial cell proliferation	1	5617.3×	0.002	ALDH1A2
retinoic acid biosynthetic process	1	4213.0×	0.002	ALDH1A2
ureter maturation	1	4213.0×	0.002	ALDH1A2
9-cis-retinoic acid biosynthetic process	1	4213.0×	0.002	ALDH1A2
vitamin A metabolic process	1	2407.4×	0.003	ALDH1A2
midgut development	1	2106.5×	0.003	ALDH1A2
morphogenesis of embryonic epithelium	1	1532.0×	0.003	ALDH1A2
aldehyde metabolic process	1	1296.3×	0.003	ALDH1A2
embryonic camera-type eye development	1	1203.7×	0.003	ALDH1A2
hindbrain development	1	1123.5×	0.003	ALDH1A2
response to vitamin A	1	1053.2×	0.003	ALDH1A2
embryonic digestive tract development	1	991.3×	0.003	ALDH1A2
retinal metabolic process	1	936.2×	0.003	ALDH1A2
cardiac muscle tissue development	1	887.0×	0.003	ALDH1A2
neural crest cell development	1	802.5×	0.003	ALDH1A2
retinoic acid metabolic process	1	802.5×	0.003	ALDH1A2
face development	1	802.5×	0.003	ALDH1A2
pancreas development	1	674.1×	0.003	ALDH1A2
proximal/distal pattern formation	1	648.1×	0.003	ALDH1A2
pituitary gland development	1	648.1×	0.003	ALDH1A2
retinoic acid receptor signaling pathway	1	648.1×	0.003	ALDH1A2
neural tube development	1	526.6×	0.003	ALDH1A2
embryonic forelimb morphogenesis	1	495.6×	0.003	ALDH1A2
retinol metabolic process	1	495.6×	0.003	ALDH1A2
response to retinoic acid	1	383.0×	0.004	ALDH1A2
blood vessel development	1	374.5×	0.004	ALDH1A2
somitogenesis	1	374.5×	0.004	ALDH1A2
heart morphogenesis	1	374.5×	0.004	ALDH1A2
response to cytokine	1	374.5×	0.004	ALDH1A2

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
ALDH1A2	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
ALDH1A2	32	Binding:32

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDH1A2	1.2.1.36	retinal dehydrogenase

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	1	ALDH1A2
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)
ALDH1A2	32	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.