Ventricular septal defect 1

Summary

Ventricular septal defect 1 (MONDO:0013746) is a disease with 5 cohort genes.

At a glance

• Cohort genes: 5
• ClinVar variants: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ventricular septal defect 1
Mondo ID	MONDO:0013746
OMIM	614429
UMLS	C3280777
MedGen	482407
Is cancer (heuristic)	no

Also known as: GATA4 ventricular septal defect (disease) · ventricular septal defect (disease) caused by mutation in GATA4 · ventricular septal defect 1 · ventricular septal defect type 1 · VSD1

Data availability: 31 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › congenital heart disease › heart septal defect › ventricular septal defect › ventricular septal defect 1

Related subtypes (4): ventricular septal defect 2, ventricular septal defect 3, double outlet right ventricle, anterior deviation infundibular septum

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

31 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 9 pathogenic, 5 conflicting classifications of pathogenicity, 2 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2574129	NM_001200.4(BMP2):c.982G>A (p.Glu328Lys)	BMP2	Pathogenic	no assertion criteria provided
1702933	NM_001719.3(BMP7):c.254A>T (p.Asp85Val)	BMP7	Pathogenic	no assertion criteria provided
2574124	NM_001077415.3(CRELD1):c.587G>T (p.Gly196Val)	CRELD1	Pathogenic	no assertion criteria provided
2574126	NM_001077415.3(CRELD1):c.1049-401C>A	CRELD1	Pathogenic	no assertion criteria provided
1338850	NM_001308093.3(GATA4):c.691C>T (p.Arg231Ter)	GATA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1452170	NM_001308093.3(GATA4):c.54C>G (p.Tyr18Ter)	GATA4	Pathogenic	criteria provided, single submitter
30106	NM_001308093.3(GATA4):c.889G>C (p.Gly297Arg)	GATA4	Pathogenic	no assertion criteria provided
2574127	NM_016358.3(IRX4):c.71G>A (p.Ser24Asn)	IRX4	Pathogenic	no assertion criteria provided
2574128	NM_016358.3(IRX4):c.572C>T (p.Thr191Ile)	IRX4	Pathogenic	no assertion criteria provided
30099	NM_001308093.3(GATA4):c.487C>T (p.Pro163Ser)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30101	NM_001308093.3(GATA4):c.1078G>A (p.Glu360Lys)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30103	NM_001308093.3(GATA4):c.1223C>A (p.Pro408Gln)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
44336	NM_001308093.3(GATA4):c.825C>T (p.Cys275=)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9034	NM_001308093.3(GATA4):c.1276G>A (p.Asp426Asn)	GATA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029406	NM_001308093.3(GATA4):c.931A>T (p.Met311Leu)	GATA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1197085	NM_001308093.3(GATA4):c.1240C>G (p.Pro414Ala)	GATA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1314160	NM_001308093.3(GATA4):c.1149G>A (p.Gln383=)	GATA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1372032	NM_001308093.3(GATA4):c.623T>C (p.Met208Thr)	GATA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1444319	NM_001308093.3(GATA4):c.343G>T (p.Gly115Trp)	GATA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
30102	NM_001308093.3(GATA4):c.1328C>T (p.Ala443Val)	GATA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
30107	NM_001308093.3(GATA4):c.127C>T (p.Arg43Trp)	GATA4	Uncertain significance	criteria provided, single submitter
3595040	NM_001308093.3(GATA4):c.790G>A (p.Ala264Thr)	GATA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
424039	NM_001308093.3(GATA4):c.1315G>A (p.Asp439Asn)	GATA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
4293360	NM_001308093.3(GATA4):c.758G>C (p.Arg253Pro)	GATA4	Uncertain significance	criteria provided, single submitter
429341	NM_001308093.3(GATA4):c.392C>G (p.Ala131Gly)	GATA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
472776	NM_001308093.3(GATA4):c.263G>T (p.Gly88Val)	GATA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
472784	NM_001308093.3(GATA4):c.942G>T (p.Glu314Asp)	GATA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
518784	NM_001308093.3(GATA4):c.1318A>T (p.Ile440Leu)	GATA4	Uncertain significance	criteria provided, multiple submitters, no conflicts
195137	NM_001200.4(BMP2):c.109T>G (p.Ser37Ala)	BMP2	Benign	criteria provided, multiple submitters, no conflicts
239099	NM_001308093.3(GATA4):c.1235C>T (p.Ala412Val)	GATA4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 13 · 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
IRX4	Limited	Autosomal dominant	ventricular septal defect 1	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BMP2	Orphanet:261295	20p12.3 microdeletion syndrome
BMP2	Orphanet:93396	Brachydactyly type A2
CRELD1	Orphanet:576235	Partial atrioventricular septal defect without ventricular hypoplasia
CRELD1	Orphanet:99067	Complete atrioventricular septal defect with ventricular hypoplasia
CRELD1	Orphanet:99068	Complete atrioventricular septal defect-tetralogy of Fallot
GATA4	Orphanet:251071	8p23.1 microdeletion syndrome
GATA4	Orphanet:251510	46,XY partial gonadal dysgenesis
GATA4	Orphanet:3303	Tetralogy of Fallot
GATA4	Orphanet:334	Hereditary atrial fibrillation
GATA4	Orphanet:576232	Partial atrioventricular septal defect with ventricular hypoplasia
GATA4	Orphanet:99067	Complete atrioventricular septal defect with ventricular hypoplasia
GATA4	Orphanet:99068	Complete atrioventricular septal defect-tetralogy of Fallot
GATA4	Orphanet:99103	Atrial septal defect, ostium secundum type

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IRX4	HGNC:6129	ENSG00000113430	P78413	Iroquois-class homeodomain protein IRX-4	gencc,clinvar
BMP2	HGNC:1069	ENSG00000125845	P12643	Bone morphogenetic protein 2	clinvar
BMP7	HGNC:1074	ENSG00000101144	P18075	Bone morphogenetic protein 7	clinvar
CRELD1	HGNC:14630	ENSG00000163703	Q96HD1	Protein disulfide isomerase CRELD1	clinvar
GATA4	HGNC:4173	ENSG00000136574	P43694	Transcription factor GATA-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IRX4	Iroquois-class homeodomain protein IRX-4	Likely to be an important mediator of ventricular differentiation during cardiac development.
BMP2	Bone morphogenetic protein 2	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including cardiogenesis, neurogenesis, and osteogenesis.
BMP7	Bone morphogenetic protein 7	Growth factor of the TGF-beta superfamily that plays important role in various biological processes, including embryogenesis, hematopoiesis, neurogenesis and skeletal morphogenesis.
CRELD1	Protein disulfide isomerase CRELD1	Protein disulfide isomerase.
GATA4	Transcription factor GATA-4	Transcriptional activator that binds to the consensus sequence 5’-AGATAG-3’ and plays a key role in cardiac development and function.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 3 · 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
Transcription factor	2	3.3×	0.229
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IRX4	Transcription factor	no		HD, Iroquois_homeo, KN_HD
BMP2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
BMP7	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
CRELD1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
GATA4	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pigmented layer of retina	2
apex of heart	1
cervix squamous epithelium	1
skin of abdomen	1
cartilage tissue	1
pancreatic ductal cell	1
endometrium epithelium	1
ventricular zone	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
duodenum	1
heart left ventricle	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IRX4	93	broad	marker	skin of abdomen, apex of heart, cervix squamous epithelium
BMP2	238	broad	marker	cartilage tissue, pancreatic ductal cell, pigmented layer of retina
BMP7	243	broad	marker	pigmented layer of retina, ventricular zone, endometrium epithelium
CRELD1	134	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
GATA4	85	broad	marker	right atrium auricular region, heart left ventricle, duodenum

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GATA4	4,994
BMP7	3,134
BMP2	3,131
IRX4	1,230
CRELD1	1,018

Intra-cohort edges

A	B	Sources
BMP2	BMP7	string_interaction
CRELD1	GATA4	string_interaction
GATA4	IRX4	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BMP2	P12643	21
BMP7	P18075	4
GATA4	P43694	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CRELD1	Q96HD1	81.68
IRX4	P78413	54.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Elastic fibre formation	2	223.9×	4e-04	BMP2, BMP7
Molecules associated with elastic fibres	2	205.8×	4e-04	BMP2, BMP7
Extracellular matrix organization	2	42.1×	0.006	BMP2, BMP7
Formation of lateral plate mesoderm	1	761.3×	0.009	GATA4
Transcriptional regulation of brown and beige adipocyte differentiation	1	380.7×	0.012	BMP7
Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	1	292.8×	0.012	GATA4
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	253.8×	0.012	GATA4
Transcriptional regulation of testis differentiation	1	237.9×	0.012	GATA4
Formation of definitive endoderm	1	237.9×	0.012	GATA4
Physiological factors	1	223.9×	0.012	GATA4
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	200.3×	0.012	GATA4
Cardiogenesis	1	141.0×	0.015	GATA4
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	1	126.9×	0.016	BMP7
Signaling by BMP	1	119.0×	0.016	BMP2
Developmental Lineage of Pancreatic Acinar Cells	1	100.2×	0.017	GATA4
Transcriptional regulation by RUNX2	1	84.6×	0.019	BMP2
Developmental Lineage of Pancreatic Ductal Cells	1	76.1×	0.020	GATA4
Regulation of RUNX2 expression and activity	1	60.4×	0.024	BMP2
Adipogenesis	1	52.1×	0.026	BMP7
Signaling by TGFB family members	1	38.5×	0.034	BMP2
Factors involved in megakaryocyte development and platelet production	1	22.1×	0.055	GATA4
RNA Polymerase II Transcription	1	7.5×	0.151	BMP2
Gene expression (Transcription)	1	6.0×	0.180	BMP2
Generic Transcription Pathway	1	5.0×	0.201	BMP2
Developmental Biology	1	4.8×	0.201	BMP7
Signal Transduction	1	3.4×	0.267	BMP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic heart tube anterior/posterior pattern specification	2	2246.9×	4e-05	BMP2, GATA4
mesenchyme development	2	963.0×	9e-05	BMP2, BMP7
ameloblast differentiation	2	842.6×	9e-05	BMP2, BMP7
mesenchymal cell differentiation	2	842.6×	9e-05	BMP2, BMP7
endocardial cushion development	2	561.7×	1e-04	CRELD1, GATA4
endocardial cushion formation	2	561.7×	1e-04	BMP2, BMP7
positive regulation of DNA-templated transcription	4	22.4×	2e-04	IRX4, BMP2, BMP7, GATA4
heart development	3	47.2×	5e-04	IRX4, BMP2, BMP7
cellular response to BMP stimulus	2	224.7×	6e-04	BMP2, BMP7
positive regulation of bone mineralization	2	156.8×	0.001	BMP2, BMP7
positive regulation of SMAD protein signal transduction	2	153.2×	0.001	BMP2, BMP7
positive regulation of epithelial to mesenchymal transition	2	127.2×	0.001	BMP2, BMP7
epithelial to mesenchymal transition	2	124.8×	0.001	BMP2, BMP7
odontogenesis of dentin-containing tooth	2	120.4×	0.001	BMP2, BMP7
cell fate commitment	2	118.3×	0.001	BMP2, GATA4
negative regulation of cell cycle	2	116.2×	0.001	BMP2, BMP7
positive regulation of osteoblast differentiation	2	89.9×	0.002	BMP2, BMP7
establishment of animal organ orientation	1	3370.4×	0.002	IRX4
negative regulation of calcium-independent cell-cell adhesion	1	3370.4×	0.002	BMP2
negative regulation of mesenchymal cell apoptotic process involved in nephron morphogenesis	1	3370.4×	0.002	BMP7
mesenchymal cell apoptotic process involved in nephron morphogenesis	1	3370.4×	0.002	BMP7
BMP signaling pathway	2	80.2×	0.002	BMP2, BMP7
positive regulation of neuron differentiation	2	79.3×	0.002	BMP2, BMP7
endodermal-mesodermal cell signaling	1	1685.2×	0.004	BMP2
cardiac atrium formation	1	1685.2×	0.004	BMP2
atrial septum secundum morphogenesis	1	1685.2×	0.004	GATA4
cardiocyte differentiation	1	1685.2×	0.004	BMP2
negative regulation of glomerular mesangial cell proliferation	1	1685.2×	0.004	BMP7
nephrogenic mesenchyme morphogenesis	1	1685.2×	0.004	BMP7
mesenchymal cell proliferation involved in ureteric bud development	1	1685.2×	0.004	BMP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IRX4	0	0
BMP2	0	0
BMP7	0	0
CRELD1	0	0
GATA4	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
BMP2	22	Binding:18, Functional:4
GATA4	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	5	IRX4, BMP2, BMP7, CRELD1, GATA4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IRX4	0	—
BMP2	22	—
BMP7	0	—
CRELD1	0	—
GATA4	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.