TBX20

Summary

TBX20 (T-box transcription factor 20, HGNC:11598) is a protein-coding gene on chromosome 7p14.2, encoding T-box transcription factor TBX20 (Q9UMR3). 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.

This gene encodes a T-box family member. The T-box family members share a common DNA binding domain, termed the T-box, and they are transcription factors involved in the regulation of developmental processes. This gene is essential for heart development. Mutations in this gene are associated with diverse cardiac pathologies, including defects in septation, valvulogenesis and cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 57057 — RefSeq curated summary.

At a glance

• Gene–disease (curated): atrial septal defect 4 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 767 total — 32 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 39
• Dosage sensitivity (ClinGen): haploinsufficiency emerging evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001077653

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11598
Approved symbol	TBX20
Name	T-box transcription factor 20
Location	7p14.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000164532
Ensembl biotype	protein_coding
OMIM	606061
Entrez	57057

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 retained_intron

ENST00000408931, ENST00000492961

RefSeq mRNA: 2 — MANE Select: NM_001077653 NM_001077653, NM_001166220

CCDS: CCDS43568

Canonical transcript exons

ENST00000408931 — 8 exons

Exon	Start	End
ENSE00001332935	35253494	35254100
ENSE00001615768	35202430	35202770
ENSE00001702007	35204470	35204582
ENSE00002066597	35231504	35231580
ENSE00003492702	35249951	35250203
ENSE00003515772	35248677	35248841
ENSE00003550405	35240879	35241037
ENSE00003662090	35244949	35245057

Expression profiles

Bgee: expression breadth broad, 52 present calls, max score 89.15.

FANTOM5 (CAGE): breadth broad, TPM avg 4.3550 / max 921.8610, expressed in 503 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83542	4.0642	490
83541	0.2285	148
83543	0.0313	5
83539	0.0222	5
83540	0.0088	3

Top tissues by expression

227 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right atrium auricular region	UBERON:0006631	89.15	gold quality
cardiac atrium	UBERON:0002081	87.92	gold quality
heart	UBERON:0000948	79.29	gold quality
heart left ventricle	UBERON:0002084	78.84	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.66	gold quality
cardiac ventricle	UBERON:0002082	77.55	gold quality
apex of heart	UBERON:0002098	75.11	gold quality
right coronary artery	UBERON:0001625	72.32	gold quality
gall bladder	UBERON:0002110	71.85	gold quality
left coronary artery	UBERON:0001626	67.81	gold quality
coronary artery	UBERON:0001621	66.67	gold quality
urinary bladder	UBERON:0001255	66.03	gold quality
ascending aorta	UBERON:0001496	50.19	gold quality
thoracic aorta	UBERON:0001515	49.21	gold quality
adrenal tissue	UBERON:0018303	48.60	gold quality
placenta	UBERON:0001987	48.22	gold quality
pituitary gland	UBERON:0000007	46.69	gold quality
liver	UBERON:0002107	45.75	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
adenohypophysis	UBERON:0002196	42.15	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
nasal cavity epithelium	UBERON:0005384	41.30	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
amniotic fluid	UBERON:0000173	40.69	gold quality
subthalamic nucleus	UBERON:0001906	40.68	gold quality
jejunal mucosa	UBERON:0000399	40.59	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.42

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
FGF10	Unknown
MEF2C	Unknown
NKX2-5	Unknown
NPPA
PPARG	Activation
SORBS3	Repression
TBX2	Repression
TBX20

JASPAR motifs

Motif	Name	Family
MA0689.1	TBX20	TBX1-related factors

JASPAR matrix evidence (PMIDs): PMID:23326246

Upstream regulators (CollecTRI, top): GATA5, PITX2, SOX9, TBX20, TBX2, TP63, TWIST1

Functional genomics

ClinGen dosage: haploinsufficiency 2 (emerging evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 37)

• Our findings are the first to link TBX20 mutations to human pathology (PMID:17668378)
• analysis of TBX20 in human hearts and its regulation by TFAP2 (PMID:18275040)
• findings provide the first insight into TBX20 mutations for tetrology of fallot and anomalous pulmonary venous connection (PMID:18834961)
• These data highlight unique features of Tbx20 and suggest mechanistic ways in which cardiac T-box factors might interact synergistically and/or competitively within the cardiac regulatory network. (PMID:19414016)
• Found tertiary hydrophobic interactions within the mutant TBX20 T-box of Ostium secundum atrial septal defect subjects were significantly altered leading to a more dynamic structure of the protein. (PMID:19762328)
• This novel interaction between TBX20b and MKLN1 may help elucidate new regulatory mechanisms within heart development. (PMID:21586270)
• Study identified one novel heterozygous sequence variant within the proximal promoter region of TBX20 gene in a ventricular septal defects patient, which inhibited transcriptional activities of TBX20 gene promoter; data provide new information to help understanding of genetic causes and molecular mechanisms of congenital heart disease. (PMID:22465533)
• Tbx20 functions as an important regulator of estrogen-mediated cardiomyocyte protection during oxidative stress. (PMID:23871353)
• Tbx20 regulated PPAR-gamma expression and protected the vascular endothelial cells from oxidized low-density lipoprotein -induced injury. (PMID:24247152)
• A novel TBX20 mutation, c.526G>A (p.D176N), was identified and co-segregated in all affected members in this family of three generations with atrial septal defects. (PMID:25183037)
• Data showed that the TC genotype of SNP rs3999941 and AC genotype of the new SNP c.657A>C in the TBX20 gene may be risk factors for CHD. (PMID:25487630)
• TBX20 loss-of-function mutation contributes to double outlet right ventricle (PMID:25625280)
• We report three missense mutations (Y309D, T370O, and M395R) within the transcriptional activator domain of human TBX20 that were associated with atrial septal defect (PMID:25834824)
• The mutation markedly reduced the synergistic activation of TBX20 with NKX2-5 or GATA4. (PMID:26118961)
• Cardiac TBX20 expression showed a negative correlation with LVEF and a positive correlation with left ventricular end-systolic volume. No significant difference in TBX20 CNVs and promoter methylation was observed between IDCM patients and control group (PMID:26895318)
• Among the 8 SNPs identified, 6 are in strong linkage disequilibrium and the minor alleles are associated with lower CHD risk. The minor alleles have lower transcriptional activity than major alleles in both human heart tissues and three cell lines. TBX20 minor alleles may exhibit higher binding affinity with certain transcription repressors. (PMID:27034249)
• rs3999950 may be associated with congenital heart disease, and TBX20 may predispose children to the defect. (PMID:27323105)
• chromatin analysis reveals that endocardial TBX20 has roles in septation (PMID:27348591)
• The current study associated TBX20 haploinefficiency with isolated Dilated cardiomyopathy (DCM), and expanded upon the mutational spectrum of TBX20 associated with DCM and congenital heart disease (CHD), which provides novel insight into the molecular mechanism of DCM and CHD, suggesting potential implications for early personalized treatment of these diseases. (PMID:27510170)
• Silencing of TBX20 in rat myocardial and human embryonic kidney cells significantly inhibited cell proliferation, induced cell apoptosis and led to G2/M cell cycle arrest. (PMID:27572266)
• TBX20 can be considered a KCNH2-modifying gene. (PMID:28049825)
• results showed that the TBX20 gene is not the major gene affecting nonsyndromic congenital heart disease development (PMID:28525297)
• This study firstly links TBX20 loss-of-function mutation to familial tetralogy of Fallot or sporadic persistent truncus arteriosus, providing novel insight into the molecular pathogenesis of Congenital heart disease. (PMID:28553164)
• Collectively, our proteomic, biochemical, genetic, and structural studies suggest that the physical interaction between TBX20 and CASZ1 is required for cardiac homeostasis, and further, that reduction or loss of this critical interaction leads to dilated cardiomyopathy (DCM) (PMID:28945738)
• The downregulated methylation level at TBX20 promoter may be responsible for the elevated mRNA expression levels in patients with tetralogy of Fallot. (PMID:30084275)
• accumulative evidence for TBX20 involvement in Bicuspid aortic valve /aortic aneurysms aetiology underlines the importance of this transcription factor in cardiovascular disease. (PMID:30820038)
• DNA methylation status of TBX20 in patients with tetralogy of Fallot (PMID:31138201)
• Genetic variants of the TBX20 and AXIN1 genes confer a significantly increased risk of congenital septal heart defects in a population from Northeastern Mexico. (PMID:31524541)
• The Double Mutation DSG2-p.S363X and TBX20-p.D278X Is Associated with Left Ventricular Non-Compaction Cardiomyopathy: Case Report. (PMID:34202524)
• Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries. (PMID:34886679)
• Familial cardiac septal defect due to a novel nine-base deletion in TBX20. (PMID:35298876)
• TBX20 inhibits colorectal cancer tumorigenesis by impairing NHEJ-mediated DNA repair. (PMID:35348274)
• TBX20 Improves Contractility and Mitochondrial Function During Direct Human Cardiac Reprogramming. (PMID:36102189)
• Epigenetic Evaluation of the TBX20 Gene and Environmental Risk Factors in Mexican Paediatric Patients with Congenital Septal Defects. (PMID:36831251)
• TBX20 loss-of-function variants in families with left ventricular non-compaction cardiomyopathy. (PMID:37657916)
• Genetic and functional variants of the TBX20 gene promoter in dilated cardiomyopathy. (PMID:38284443)
• Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction. (PMID:38353104)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbx20	ENSDARG00000005150
mus_musculus	Tbx20	ENSMUSG00000031965
rattus_norvegicus	Tbx20	ENSRNOG00000016181
drosophila_melanogaster	H15	FBGN0016660
drosophila_melanogaster	mid	FBGN0261963
drosophila_melanogaster	ocm	FBGN0266083
caenorhabditis_elegans		WBGENE00003106
caenorhabditis_elegans		WBGENE00004750
caenorhabditis_elegans		WBGENE00006545
caenorhabditis_elegans		WBGENE00006546
caenorhabditis_elegans		WBGENE00006556
caenorhabditis_elegans		WBGENE00006557
caenorhabditis_elegans		WBGENE00006559
caenorhabditis_elegans		WBGENE00044798

Paralogs (16): TBX21 (ENSG00000073861), TBX5 (ENSG00000089225), TBX15 (ENSG00000092607), TBX18 (ENSG00000112837), TBX2 (ENSG00000121068), TBX4 (ENSG00000121075), TBX22 (ENSG00000122145), TBX3 (ENSG00000135111), TBR1 (ENSG00000136535), TBX19 (ENSG00000143178), TBX6 (ENSG00000149922), EOMES (ENSG00000163508), TBXT (ENSG00000164458), TBX10 (ENSG00000167800), MGA (ENSG00000174197), TBX1 (ENSG00000184058)

Protein

Protein identifiers

T-box transcription factor TBX20 — Q9UMR3 (reviewed: Q9UMR3)

All UniProt accessions (1): Q9UMR3

UniProt curated annotations — full annotation on UniProt →

Function. 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.

Subcellular location. Nucleus.

Disease relevance. Atrial septal defect 4 (ASD4) [MIM:611363] A congenital heart malformation characterized by incomplete closure of the wall between the atria resulting in blood flow from the left to the right atria. Patients show other heart abnormalities including defects in septation, chamber growth and valvulogenesis. The disease is not associated with defects in the cardiac conduction system or with non-cardiac abnormalities. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (2): NP_001071121, NP_001159692 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001699	TF_T-box	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR018186	TF_T-box_CS	Conserved_site
IPR036960	T-box_sf	Homologous_superfamily
IPR046360	T-box_DNA-bd	Domain

Pfam: PF00907

UniProt features (7 total): region of interest 2, sequence variant 2, chain 1, DNA-binding region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UMR3-F1	67.87	0.39

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9733709	Cardiogenesis
R-HSA-1266738	Developmental Biology

MSigDB gene sets: 290 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, WWTAAGGC_UNKNOWN, GOBP_OUTFLOW_TRACT_SEPTUM_MORPHOGENESIS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER

GO Biological Process (46): negative regulation of transcription by RNA polymerase II (GO:0000122), branching involved in blood vessel morphogenesis (GO:0001569), endoderm formation (GO:0001706), cell fate specification (GO:0001708), heart looping (GO:0001947), embryonic heart tube morphogenesis (GO:0003143), outflow tract septum morphogenesis (GO:0003148), atrioventricular valve development (GO:0003171), tricuspid valve development (GO:0003175), aortic valve morphogenesis (GO:0003180), pulmonary valve formation (GO:0003193), endocardial cushion morphogenesis (GO:0003203), cardiac chamber formation (GO:0003207), cardiac right ventricle morphogenesis (GO:0003215), endocardial cushion formation (GO:0003272), cardiac septum development (GO:0003279), pericardium morphogenesis (GO:0003344), regulation of transcription by RNA polymerase II (GO:0006357), muscle contraction (GO:0006936), blood circulation (GO:0008015), cell population proliferation (GO:0008283), dorsal/ventral pattern formation (GO:0009953), positive regulation of epithelial to mesenchymal transition (GO:0010718), mesenchymal cell development (GO:0014031), visceral motor neuron differentiation (GO:0021524), positive regulation of BMP signaling pathway (GO:0030513), foramen ovale closure (GO:0035922), atrioventricular canal development (GO:0036302), embryonic heart tube elongation (GO:0036306), positive regulation of apoptotic process (GO:0043065), negative regulation of DNA-templated transcription (GO:0045892), lateral mesoderm formation (GO:0048370), cardiac muscle tissue morphogenesis (GO:0055008), positive regulation of cardiac muscle cell proliferation (GO:0060045), negative regulation of SMAD protein signal transduction (GO:0060392), atrial septum morphogenesis (GO:0060413), pulmonary vein morphogenesis (GO:0060577), positive regulation of cell cycle process (GO:0090068), motor neuron migration (GO:0097475), outflow tract morphogenesis (GO:0003151)

GO Molecular Function (8): RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
heart morphogenesis	2
embryonic morphogenesis	2
anatomical structure formation involved in morphogenesis	2
regulation of DNA-templated transcription	2
transcription cis-regulatory region binding	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
angiogenesis	1
blood vessel morphogenesis	1
branching morphogenesis of an epithelial tube	1
formation of primary germ layer	1
endoderm development	1
cell fate commitment	1
cellular developmental process	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
embryonic heart tube development	1
embryonic organ morphogenesis	1
epithelial tube morphogenesis	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
heart valve development	1
atrioventricular valve development	1
aortic valve development	1
heart valve morphogenesis	1
pulmonary valve morphogenesis	1
heart valve formation	1
endocardial cushion development	1
mesenchyme morphogenesis	1
cardiac chamber morphogenesis	1
cardiac ventricle morphogenesis	1
endocardial cushion morphogenesis	1
cardiac chamber development	1
anatomical structure development	1
morphogenesis of an epithelial sheet	1
pericardium development	1
muscle system process	1

Protein interactions and networks

STRING

1346 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBX20	NKX2-5	P52952	990
TBX20	GATA4	P43694	990
TBX20	HAND2	P61296	861
TBX20	GATA6	P78327	793
TBX20	MYH6	P13533	776
TBX20	GATA5	Q9BWX5	737
TBX20	TLL1	O43897	703
TBX20	ZFPM2	Q8WW38	700
TBX20	TNNT2	P45379	692
TBX20	ISL1	P20663	690
TBX20	ACTC1	P04270	690
TBX20	MEIS1	O00470	657
TBX20	MEF2C	Q06413	635
TBX20	SMARCD3	Q6STE5	627
TBX20	ZFPM1	Q8IX07	571

IntAct

38 interactions, top by confidence:

A	B	Type	Score
SLC19A2	ATP5F1B	psi-mi:“MI:0914”(association)	0.730
BLVRA	DDHD2	psi-mi:“MI:0914”(association)	0.530
PHF13	DNASE1L2	psi-mi:“MI:0914”(association)	0.530
SLC25A21	DNASE1L2	psi-mi:“MI:0914”(association)	0.530
	TBX20	psi-mi:“MI:0915”(physical association)	0.370
CCL3L1	TBX20	psi-mi:“MI:0915”(physical association)	0.370
IFNG	TBX20	psi-mi:“MI:0915”(physical association)	0.370
IL17A	TBX20	psi-mi:“MI:0915”(physical association)	0.370
PF4V1	TBX20	psi-mi:“MI:0915”(physical association)	0.370
XCL1	TBX20	psi-mi:“MI:0915”(physical association)	0.370
TBX20	ZSCAN1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (41): TBX20 (Affinity Capture-MS), TBX20 (Affinity Capture-MS), TBX20 (Affinity Capture-MS), TLE1 (Affinity Capture-MS), TLE3 (Affinity Capture-MS), TLE4 (Affinity Capture-MS), TBX20 (Affinity Capture-MS), TBX20 (Affinity Capture-MS), TBX20 (Affinity Capture-MS), TLE4 (Affinity Capture-MS), TLE3 (Affinity Capture-MS), TLE1 (Affinity Capture-MS), DNASE1L2 (Affinity Capture-MS), TBX20 (Negative Genetic), TBX20 (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q0KHE7, A3KPF2, B0W3L6, B4JXV2, B4KA23, B4LVS8, D9PTN5, G5EFI7, H2KYJ8, M9PD06, O45666, O88898, P10383, P49881, P51592, P79926, Q08639, Q09441, Q14149, Q14186, Q17370, Q174R2, Q18192, Q21006, Q23985, Q24143, Q28CK1, Q3SA46, Q66J63, Q6E3C9, Q6E3D0, Q6GN21, Q7Q2B7, Q84W92, Q86NH1, Q8AXW8, Q8UW76, Q91766, Q94527, Q95YE2

Diamond homologs: A1YF56, A2AWL7, D3ZJK7, E1BEA8, O01409, O13161, O15119, O15178, O17212, O43435, O54839, O60806, O70306, O73718, O75333, O95935, O95936, O95947, P20293, P24781, P55965, P56158, P57082, P70323, P70324, P70325, P70326, P70327, P79742, P79777, P79778, P79779, P79944, P80492, P87377, P90971, Q07998, Q13207, Q16650, Q17134

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 19 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
inflammatory response	5	10.5×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

767 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	32
Likely pathogenic	13
Uncertain significance	441
Likely benign	232
Benign	20

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1350837	NM_001077653.2(TBX20):c.935C>A (p.Ser312Ter)	Pathogenic
1378678	NM_001077653.2(TBX20):c.270dup (p.Ile91fs)	Pathogenic
1426621	NM_001077653.2(TBX20):c.853G>T (p.Gly285Ter)	Pathogenic
1436482	NM_001077653.2(TBX20):c.403del (p.Val135fs)	Pathogenic
1468168	NM_001077653.2(TBX20):c.118A>T (p.Lys40Ter)	Pathogenic
1485919	NM_001077653.2(TBX20):c.418del (p.Val140fs)	Pathogenic
1486963	NM_001077653.2(TBX20):c.697dup (p.Ile233fs)	Pathogenic
1736104	NM_001077653.2(TBX20):c.390dup (p.Pro131fs)	Pathogenic
2006880	NM_001077653.2(TBX20):c.955G>T (p.Gly319Ter)	Pathogenic
2026375	NM_001077653.2(TBX20):c.484del (p.Tyr162fs)	Pathogenic
2057023	NM_001077653.2(TBX20):c.367dup (p.Thr123fs)	Pathogenic
2068981	NM_001077653.2(TBX20):c.748G>T (p.Glu250Ter)	Pathogenic
2103183	NM_001077653.2(TBX20):c.552T>G (p.Tyr184Ter)	Pathogenic
2155255	NM_001077653.2(TBX20):c.614del (p.Lys205fs)	Pathogenic
2423623	NC_000007.13:g.(?35271096)(35293231_?)del	Pathogenic
2719404	NM_001077653.2(TBX20):c.776del (p.Thr259fs)	Pathogenic
2754523	NM_001077653.2(TBX20):c.526_539del (p.Asp176fs)	Pathogenic
2769758	NM_001077653.2(TBX20):c.413dup (p.Val140fs)	Pathogenic
2834950	NM_001077653.2(TBX20):c.595C>T (p.Gln199Ter)	Pathogenic
2839135	NM_001077653.2(TBX20):c.486C>A (p.Tyr162Ter)	Pathogenic
2848378	NM_001077653.2(TBX20):c.512_518del (p.Val171fs)	Pathogenic
3644712	NM_001077653.2(TBX20):c.490_493dup (p.His165fs)	Pathogenic
3651568	NM_001077653.2(TBX20):c.110del (p.Asn37fs)	Pathogenic
3727062	NM_001077653.2(TBX20):c.533del (p.Pro178fs)	Pathogenic
438266	NM_001077653.2(TBX20):c.995del (p.Pro332fs)	Pathogenic
4532066	NM_001077653.2(TBX20):c.833_836del (p.Asp278fs)	Pathogenic
4633	NM_001077653.2(TBX20):c.583C>T (p.Gln195Ter)	Pathogenic
4634	NM_001077653.2(TBX20):c.363C>G (p.Ile121Met)	Pathogenic
4716398	NM_001077653.2(TBX20):c.357_361dup (p.Ile121delinsArgTer)	Pathogenic
4722730	NM_001077653.2(TBX20):c.61del (p.Ala21fs)	Pathogenic

SpliceAI

1217 predictions. Top by Δscore:

Variant	Effect	Δscore
7:35204465:CTTA:C	donor_loss	1.0000
7:35204466:TTA:T	donor_loss	1.0000
7:35204467:TACCT:T	donor_loss	1.0000
7:35204468:ACCT:A	donor_loss	1.0000
7:35204469:CC:C	donor_loss	1.0000
7:35231498:CATTA:C	donor_loss	1.0000
7:35231499:ATTAC:A	donor_loss	1.0000
7:35231500:TTA:T	donor_loss	1.0000
7:35231501:TAC:T	donor_loss	1.0000
7:35231502:A:AG	donor_loss	1.0000
7:35231503:C:A	donor_loss	1.0000
7:35231503:CCT:C	donor_gain	1.0000
7:35240874:CTCA:C	donor_loss	1.0000
7:35240875:TCAC:T	donor_loss	1.0000
7:35240876:CACC:C	donor_loss	1.0000
7:35240877:ACCAG:A	donor_loss	1.0000
7:35240878:C:G	donor_loss	1.0000
7:35241034:TTAT:T	acceptor_gain	1.0000
7:35244941:GTACT:G	donor_loss	1.0000
7:35244942:TACTT:T	donor_loss	1.0000
7:35244944:CT:C	donor_loss	1.0000
7:35244945:TT:T	donor_loss	1.0000
7:35244946:TA:T	donor_loss	1.0000
7:35244947:A:AC	donor_gain	1.0000
7:35244947:A:AG	donor_loss	1.0000
7:35244948:C:CC	donor_gain	1.0000
7:35244948:CA:C	donor_gain	1.0000
7:35244948:CATG:C	donor_gain	1.0000
7:35244948:CATGG:C	donor_gain	1.0000
7:35245058:C:CG	acceptor_loss	1.0000

AlphaMissense

2926 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:35231531:T:A	D288V	1.000
7:35231531:T:G	D288A	1.000
7:35231532:C:G	D288H	1.000
7:35231534:C:A	R287L	1.000
7:35231534:C:G	R287P	1.000
7:35231534:C:T	R287Q	1.000
7:35231535:G:A	R287W	1.000
7:35231535:G:C	R287G	1.000
7:35231536:G:C	F286L	1.000
7:35231536:G:T	F286L	1.000
7:35231537:A:C	F286C	1.000
7:35231537:A:G	F286S	1.000
7:35231538:A:C	F286V	1.000
7:35231538:A:G	F286L	1.000
7:35231538:A:T	F286I	1.000
7:35231540:C:A	G285V	1.000
7:35231540:C:G	G285A	1.000
7:35231540:C:T	G285E	1.000
7:35231541:C:G	G285R	1.000
7:35231541:C:T	G285R	1.000
7:35231542:T:A	K284N	1.000
7:35231542:T:G	K284N	1.000
7:35231543:T:A	K284I	1.000
7:35231543:T:G	K284T	1.000
7:35231544:T:C	K284E	1.000
7:35231544:T:G	K284Q	1.000
7:35231546:G:A	A283V	1.000
7:35231546:G:C	A283G	1.000
7:35231546:G:T	A283D	1.000
7:35231547:C:G	A283P	1.000

dbSNP variants (sampled 300 via entrez): RS1000179646 (7:35209391 G>T), RS1000343707 (7:35217708 T>C), RS1000461751 (7:35256038 G>A,T), RS1000578403 (7:35217459 A>G), RS1000596882 (7:35250340 G>A,C,T), RS1000939176 (7:35231386 T>A,C), RS1000967599 (7:35245142 A>T), RS1000978239 (7:35238932 T>G), RS1001176882 (7:35230550 G>A,T), RS1001189369 (7:35224462 C>G), RS1001287505 (7:35238731 T>C), RS1001579621 (7:35244386 A>T), RS1001799263 (7:35250901 C>T), RS1001812588 (7:35203763 T>C), RS1001897692 (7:35218041 C>A)

Disease associations

OMIM: gene MIM:606061 | disease phenotypes: MIM:611363, MIM:604169, MIM:241550, MIM:194200, MIM:109730

GenCC curated gene-disease

Disease	Classification	Inheritance
atrial septal defect 4	Definitive	Autosomal dominant
congenital heart disease	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
dilated cardiomyopathy	Strong	AD
congenital heart disease	Moderate	AD

Mondo (8): atrial septal defect 4 (MONDO:0012654), left ventricular noncompaction (MONDO:0018901), dilated cardiomyopathy (MONDO:0005021), hypoplastic left heart syndrome (MONDO:0004933), Wolff-Parkinson-White syndrome (MONDO:0008685), hypoplastic right heart syndrome (MONDO:0020291), aortic valve disease 1 (MONDO:0024523), congenital heart disease (MONDO:0005453)

Orphanet (6): Interatrial communication (Orphanet:1478), Left ventricular noncompaction (Orphanet:54260), Dilated cardiomyopathy (Orphanet:217604), Hypoplastic left heart syndrome (Orphanet:2248), Hypoplastic right heart syndrome (Orphanet:98723), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907)

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000961	Cyanosis
HP:0001279	Syncope
HP:0001297	Stroke
HP:0001631	Atrial septal defect
HP:0001633	Abnormal mitral valve morphology
HP:0001635	Congestive heart failure
HP:0001653	Mitral regurgitation
HP:0001655	Patent foramen ovale
HP:0001680	Coarctation of aorta
HP:0001708	Right ventricular failure
HP:0001962	Palpitations
HP:0002090	Pneumonia
HP:0002092	Pulmonary arterial hypertension
HP:0002094	Dyspnea
HP:0002326	Transient ischemic attack
HP:0002718	Recurrent bacterial infections
HP:0002875	Exertional dyspnea
HP:0003546	Exercise intolerance
HP:0004749	Atrial flutter
HP:0004755	Supraventricular tachycardia
HP:0005110	Atrial fibrillation
HP:0005115	Supraventricular arrhythmia
HP:0005133	Right ventricular dilatation
HP:0005162	Abnormal left ventricular function
HP:0005180	Tricuspid regurgitation
HP:0005317	Increased pulmonary vascular resistance
HP:0005957	Breathing dysregulation
HP:0006536	Airway obstruction
HP:0010741	Pedal edema

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST002969_4	Suicide behavior	8.000000e-06
GCST002973_1	Suicide	2.000000e-07
GCST003598_3	QRS duration	1.000000e-14
GCST003598_32	QRS duration	1.000000e-13
GCST003818_72	Resting heart rate	3.000000e-12
GCST003844_22	QRS duration	7.000000e-18
GCST005146_42	Birth weight	1.000000e-08
GCST005194_241	Coronary artery disease	3.000000e-07
GCST006627_94	Diastolic blood pressure	3.000000e-15
GCST007045_29	PR interval	4.000000e-10
GCST007227_10	QRS duration	1.000000e-09
GCST008362_113	Birth weight	1.000000e-08
GCST010321_118	PR interval	6.000000e-22
GCST010796_5109	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-15
GCST010796_5110	Electrocardiogram morphology (amplitude at temporal datapoints)	9.000000e-15
GCST010866_123	Coronary artery disease	8.000000e-11
GCST011365_27	Myocardial infarction	6.000000e-07
GCST90086158_11	Brugada syndrome	4.000000e-11
GCST90086158_12	Brugada syndrome	2.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007623	suicide behaviour
EFO:0007624	suicide
EFO:0005054	QRS complex
EFO:0004344	birth weight
EFO:0006336	diastolic blood pressure
EFO:0004462	PR interval
EFO:0004327	electrocardiography

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D018636	Hypoplastic Left Heart Syndrome	C14.240.400.625; C14.280.400.625; C16.131.240.400.625
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C566963	Atrial Septal Defect 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
terbufos	increases methylation	1
arsenite	increases methylation	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	decreases expression, increases reaction	1
Acetaminophen	increases expression	1
Cadmium	decreases expression	1
Cisplatin	decreases expression, increases reaction	1
Diethylhexyl Phthalate	increases methylation, increases abundance	1
Fonofos	increases methylation	1
Methapyrilene	increases methylation	1
Parathion	increases methylation	1
Triclosan	decreases expression	1
Valproic Acid	decreases methylation	1
Vanadates	decreases expression	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C9JC	WAe009-A-84	Embryonic stem cell	Female
CVCL_D6SC	WAe009-A-1E	Embryonic stem cell	Female

Clinical trials (associated diseases)

518 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00333827	PHASE3	COMPLETED	Cell Therapy In Dilated Cardiomyopathy
NCT00505154	PHASE3	COMPLETED	Effect of Rosuvastatin on Left Ventricular Remodeling
NCT01223703	PHASE3	COMPLETED	PUFAs and Left Ventricular Function in Heart Failure
NCT01583114	PHASE3	TERMINATED	PREclinical Mutation CARriers From Families With DIlated Cardiomyopathy and ACE Inhibitors
NCT01914081	PHASE3	UNKNOWN	Resveratrol: A Potential Anti- Remodeling Agent in Heart Failure, From Bench to Bedside
NCT02989181	PHASE3	UNKNOWN	Continues Positive Airway Pressure Treatment for Patients With Dilated Cardiomyopathy and Obstructive Sleep Apnea
NCT03439514	PHASE3	TERMINATED	A Study of ARRY-371797 (PF-07265803) in Patients With Symptomatic Dilated Cardiomyopathy Due to a Lamin A/C Gene Mutation