Atrial septal defect 4

Summary

Atrial septal defect 4 (MONDO:0012654) is a disease caused by TBX20 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: TBX20 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 47

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atrial septal defect 4
Mondo ID	MONDO:0012654
MeSH	C566963
OMIM	611363
DOID	DOID:0110109
UMLS	C1969657
MedGen	369556
GARD	0015512
Is cancer (heuristic)	no

Also known as: ASD4 · atrial heart septal defect caused by mutation in TBX20 · atrial heart septal defect type 4 · atrial septal defect 4 · atrial septal defect type 4 · TBX20 atrial heart septal defect

Data availability: 47 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › congenital heart disease › heart septal defect › atrial septal defect › atrial septal defect 4

Related subtypes (14): Lutembacher syndrome, atrial septal defect 1, atrial septal defect 7, atrial septal defect 2, atrial septal defect 5, atrial septal defect 6, atrial septal defect 3, atrial septal defect 8, atrial septal defect 9, atrial septal defect, ostium secundum type, atrial septal defect, coronary sinus type, atrial septal defect, sinus venosus type, atrial septal defect, ostium primum type, patent foramen ovale

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

47 retrieved; paginated sample, class counts are floors:

33 uncertain significance, 3 benign, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 likely benign, 2 pathogenic, 1 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4633	NM_001077653.2(TBX20):c.583C>T (p.Gln195Ter)	TBX20	Pathogenic	no assertion criteria provided
4634	NM_001077653.2(TBX20):c.363C>G (p.Ile121Met)	TBX20	Pathogenic	no assertion criteria provided
590957	NM_001077653.2(TBX20):c.374C>A (p.Ser125Ter)	TBX20	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3062296	NM_001077653.2(TBX20):c.654+1G>C	TBX20	Likely pathogenic	criteria provided, single submitter
4056450	NM_001077653.2(TBX20):c.526G>A (p.Asp176Asn)	TBX20	Likely pathogenic	criteria provided, single submitter
4688018	NM_001077653.2(TBX20):c.127+2_127+10del	TBX20	Likely pathogenic	criteria provided, single submitter
1303716	NM_001077653.2(TBX20):c.1046G>C (p.Trp349Ser)	TBX20	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
802304	NM_001077653.2(TBX20):c.546-8T>A	TBX20	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1181575	NM_001077653.2(TBX20):c.86C>G (p.Ser29Cys)	TBX20	Uncertain significance	criteria provided, multiple submitters, no conflicts
1187558	NM_001077653.2(TBX20):c.418G>A (p.Val140Met)	TBX20	Uncertain significance	criteria provided, multiple submitters, no conflicts
1223434	NM_001077653.2(TBX20):c.457G>A (p.Val153Ile)	TBX20	Uncertain significance	criteria provided, multiple submitters, no conflicts
1285113	NM_001077653.2(TBX20):c.4G>A (p.Glu2Lys)	TBX20	Uncertain significance	criteria provided, multiple submitters, no conflicts
1306475	NM_001077653.2(TBX20):c.413C>T (p.Ser138Leu)	TBX20	Uncertain significance	criteria provided, multiple submitters, no conflicts
132821	NM_001077653.2(TBX20):c.-517C>T	TBX20	Uncertain significance	no assertion criteria provided
132822	NM_001077653.2(TBX20):c.1003+129T>C	TBX20	Uncertain significance	no assertion criteria provided
132823	NM_001077653.2(TBX20):c.1003+99C>T	TBX20	Uncertain significance	no assertion criteria provided
132824	NM_001077653.2(TBX20):c.1108A>C (p.Thr370Pro)	TBX20	Uncertain significance	no assertion criteria provided
132825	NM_001077653.2(TBX20):c.1184T>G (p.Met395Arg)	TBX20	Uncertain significance	no assertion criteria provided
132826	NM_001077653.2(TBX20):c.1189C>T (p.Leu397=)	TBX20	Uncertain significance	no assertion criteria provided
132827	NC_000007.14:g.35202418T>A	TBX20	Uncertain significance	no assertion criteria provided
132828	NC_000007.14:g.35202417A>T	TBX20	Uncertain significance	no assertion criteria provided
132829	NC_000007.14:g.35202382A>T	TBX20	Uncertain significance	no assertion criteria provided
132830	NM_001077653.2(TBX20):c.546-1224dup	TBX20	Uncertain significance	no assertion criteria provided
132832	NM_001077653.2(TBX20):c.657A>C (p.Ile219=)	TBX20	Uncertain significance	no assertion criteria provided
132833	NM_001077653.2(TBX20):c.925T>G (p.Tyr309Asp)	TBX20	Uncertain significance	no assertion criteria provided
1388244	NM_001077653.2(TBX20):c.785C>T (p.Thr262Met)	TBX20	Uncertain significance	criteria provided, multiple submitters, no conflicts
1398868	NM_001077653.2(TBX20):c.599T>C (p.Met200Thr)	TBX20	Uncertain significance	criteria provided, multiple submitters, no conflicts
1414602	NM_001077653.2(TBX20):c.395C>T (p.Thr132Ile)	TBX20	Uncertain significance	criteria provided, multiple submitters, no conflicts
1493849	NM_001077653.2(TBX20):c.1036C>G (p.Leu346Val)	TBX20	Uncertain significance	criteria provided, multiple submitters, no conflicts
1677798	NM_001077653.2(TBX20):c.493C>T (p.His165Tyr)	TBX20	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
TBX20	Definitive	Autosomal dominant	atrial septal defect 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBX20	Orphanet:54260	Left ventricular noncompaction
TBX20	Orphanet:99103	Atrial septal defect, ostium secundum type

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
TBX20	HGNC:11598	ENSG00000164532	Q9UMR3	T-box transcription factor TBX20	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBX20	T-box transcription factor TBX20	Acts as a transcriptional activator and repressor required for cardiac development and may have key roles in the maintenance of functional and structural phenotypes in adult heart.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBX20	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS

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
cardiac atrium	1
heart	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBX20	52	broad	marker	right atrium auricular region, cardiac atrium, heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBX20	1,425

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBX20	Q9UMR3	67.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Cardiogenesis	1	423.0×	0.005	TBX20
Developmental Biology	1	14.5×	0.069	TBX20

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
tricuspid valve development	1	16852.0×	8e-04	TBX20
embryonic heart tube elongation	1	16852.0×	8e-04	TBX20
lateral mesoderm formation	1	16852.0×	8e-04	TBX20
pulmonary valve formation	1	8426.0×	8e-04	TBX20
foramen ovale closure	1	8426.0×	8e-04	TBX20
pulmonary vein morphogenesis	1	8426.0×	8e-04	TBX20
cardiac chamber formation	1	5617.3×	9e-04	TBX20
visceral motor neuron differentiation	1	5617.3×	9e-04	TBX20
atrioventricular valve development	1	4213.0×	0.001	TBX20
positive regulation of cell cycle process	1	2808.7×	0.001	TBX20
mesenchymal cell development	1	2407.4×	0.001	TBX20
pericardium morphogenesis	1	2106.5×	0.001	TBX20
embryonic heart tube morphogenesis	1	1872.4×	0.001	TBX20
cardiac septum development	1	1685.2×	0.001	TBX20
motor neuron migration	1	1685.2×	0.001	TBX20
atrioventricular canal development	1	1532.0×	0.001	TBX20
endoderm formation	1	1404.3×	0.001	TBX20
cardiac right ventricle morphogenesis	1	1404.3×	0.001	TBX20
endocardial cushion formation	1	1404.3×	0.001	TBX20
cardiac muscle tissue morphogenesis	1	1404.3×	0.001	TBX20
atrial septum morphogenesis	1	1296.3×	0.001	TBX20
endocardial cushion morphogenesis	1	842.6×	0.002	TBX20
outflow tract septum morphogenesis	1	648.1×	0.003	TBX20
positive regulation of cardiac muscle cell proliferation	1	624.1×	0.003	TBX20
negative regulation of SMAD protein signal transduction	1	601.9×	0.003	TBX20
branching involved in blood vessel morphogenesis	1	526.6×	0.003	TBX20
cell fate specification	1	526.6×	0.003	TBX20
blood circulation	1	510.7×	0.003	TBX20
positive regulation of BMP signaling pathway	1	455.5×	0.003	TBX20
aortic valve morphogenesis	1	432.1×	0.003	TBX20

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TBX20	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TBX20

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)
TBX20	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.