Transposition of the great arteries

Summary

Transposition of the great arteries (MONDO:0000153) is a disease with 3 cohort genes (2 GWAS associations across 1 studies) and 32 clinical trials. Top therapeutic interventions include eplerenone and nitric oxide.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Cohort genes: 3
• GWAS associations: 2
• ClinVar variants: 3
• Clinical trials: 32

Clinical features

Epidemiology

Prevalence records

18 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-5 / 10 000	31.7	Europe	Validated
Prevalence at birth	1-5 / 10 000	50	United States	Validated
Prevalence at birth	1-5 / 10 000	23.3	Belgium	Validated
Prevalence at birth	1-5 / 10 000	59.5	Denmark	Validated
Prevalence at birth	1-5 / 10 000	33.4	France	Validated
Prevalence at birth	1-5 / 10 000	47.5	Germany	Validated
Prevalence at birth	1-5 / 10 000	28.8	Hungary	Validated
Prevalence at birth	1-5 / 10 000	18.1	Ireland	Validated
Prevalence at birth	1-5 / 10 000	22.6	Italy	Validated
Prevalence at birth	1-5 / 10 000	40.9	Netherlands	Validated
Prevalence at birth	1-5 / 10 000	31.1	Norway	Validated
Prevalence at birth	1-5 / 10 000	14	Poland	Validated
Prevalence at birth	1-9 / 100 000	4.7	Portugal	Validated
Prevalence at birth	1-5 / 10 000	15.7	Spain	Validated
Prevalence at birth	1-5 / 10 000	37.7	Switzerland	Validated
Prevalence at birth	1-5 / 10 000	33.9	United Kingdom	Validated
Prevalence at birth	1-5 / 10 000	22.3	Ukraine	Validated
Point prevalence	1-5 / 10 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	transposition of the great arteries
Mondo ID	MONDO:0000153
MeSH	D014188
Orphanet	216675
ICD-11	429190257
NCIT	C84742
UMLS	C0040761
MedGen	21245
GARD	0007795
Is cancer (heuristic)	no

Also known as: complete transposition · great vessels transposition · TGA · TGV · transposition of great vessels · transposition of the great vessels

Data availability: 3 ClinVar variants · 2 GWAS associations (1 study) · 1 cell line.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › congenital anomaly of cardiovascular system › congenital heart malformation › transposition of the great arteries

Related subtypes (25): congenital left-sided heart lesions, interventricular septum aneurysm, congenital heart defects, multiple types, 2, coronary artery congenital malformation, criss-cross heart, triatrial heart, familial idiopathic dilatation of the right atrium, cardiac diverticulum, conotruncal heart malformations, congenital mitral malformation, congenital pericardium anomaly, ectopia cordis, visceral heterotaxy, mesocardia, univentricular cardiopathy, congenital anomaly of the great arteries, Laubry-Pezzi syndrome, congenital Gerbode defect, juxtaposition of the atrial appendages, ectasia of the right atrial appendage, ectasia of the left appendage, atrial septal aneurysm, congenital acardia, congenital right-sided heart lesions, congenital heart defects, multiple types, 1, X-linked

Subtypes (3): heterotaxy, visceral, 2, autosomal, congenitally corrected transposition of the great arteries, dextro-looped transposition of the great arteries

Genetics & variants

GWAS landscape

2 GWAS associations across 1 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs150246290	1e-10	MACROD2	?	3.78
rs148563140	3e-08	RNU7-174P - RNU2-71P	?	3.42

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST011988	Lahm H	2020	399	8,486	Congenital heart disease risk loci identified by genome-wide association study in European patients.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	2

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	1
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs150246290	20	15132234	G>C	0.05	intron_variant	MACROD2	1e-10	Tier 4: intronic/intergenic
rs148563140	8	80563171	C>T		intergenic_variant	RNU7-174P - RNU2-71P	3e-08	Tier 4: intronic/intergenic

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
6747	NM_001492.6(GDF1):c.681C>A (p.Cys227Ter)	CERS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9030	NM_001308093.3(GATA4):c.889G>A (p.Gly297Ser)	GATA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
268037	46;XY;t(2;14)(p22;q24.3)dn		Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CERS1	Orphanet:424027	Progressive myoclonic epilepsy type 8
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

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	1
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CERS1	HGNC:14253	ENSG00000223802	P27544	Ceramide synthase 1	clinvar
MACROD2	HGNC:16126	ENSG00000172264	A1Z1Q3	ADP-ribose glycohydrolase MACROD2	gwas
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)
CERS1	Ceramide synthase 1	Ceramide synthase that catalyzes the transfer of the acyl chain from acyl-CoA to a sphingoid base, with high selectivity toward stearoyl-CoA (octadecanoyl-CoA; C18:0-CoA).
MACROD2	ADP-ribose glycohydrolase MACROD2	Removes ADP-ribose from aspartate and glutamate residues in proteins bearing a single ADP-ribose moiety.
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: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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)	2	8.0×	0.039
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CERS1	Enzyme (other)	yes	2.3.1.299	TLC-dom, Lag1/Lac1-like
MACROD2	Enzyme (other)	yes	3.1.1.106	Macro_dom, Macro_dom-like
GATA4	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
right frontal lobe	1
spinal cord	1
buccal mucosa cell	1
endothelial cell	1
epithelial cell of pancreas	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
CERS1	177	broad	yes	C1 segment of cervical spinal cord, right frontal lobe, spinal cord
MACROD2	214	ubiquitous	marker	endothelial cell, buccal mucosa cell, epithelial cell of pancreas
GATA4	85	broad	marker	right atrium auricular region, heart left ventricle, duodenum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GATA4	4,994
MACROD2	926
CERS1	76

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MACROD2	A1Z1Q3	4
GATA4	P43694	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CERS1	P27544	88.95

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 3 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
Formation of lateral plate mesoderm	1	1142.0×	0.006	GATA4
Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	1	439.2×	0.006	GATA4
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	380.7×	0.006	GATA4
Transcriptional regulation of testis differentiation	1	356.9×	0.006	GATA4
Formation of definitive endoderm	1	356.9×	0.006	GATA4
Physiological factors	1	335.9×	0.006	GATA4
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	300.5×	0.006	GATA4
Cardiogenesis	1	211.5×	0.007	GATA4
Developmental Lineage of Pancreatic Acinar Cells	1	150.3×	0.008	GATA4
Sphingolipid de novo biosynthesis	1	142.8×	0.008	CERS1
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.010	GATA4
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.030	GATA4

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to dithiothreitol	1	5617.3×	0.004	CERS1
atrial septum secundum morphogenesis	1	2808.7×	0.004	GATA4
cellular response to mycotoxin	1	2808.7×	0.004	CERS1
embryonic heart tube anterior/posterior pattern specification	1	1872.4×	0.004	GATA4
purine nucleoside metabolic process	1	1872.4×	0.004	MACROD2
peptidyl-glutamate ADP-deribosylation	1	1872.4×	0.004	MACROD2
brain development	2	53.0×	0.004	CERS1, MACROD2
atrioventricular valve formation	1	1404.3×	0.004	GATA4
cardiac muscle tissue regeneration	1	1404.3×	0.004	GATA4
atrial septum primum morphogenesis	1	1123.5×	0.004	GATA4
protein de-ADP-ribosylation	1	1123.5×	0.004	MACROD2
atrioventricular node development	1	936.2×	0.005	GATA4
cell growth involved in cardiac muscle cell development	1	802.5×	0.005	GATA4
transdifferentiation	1	702.2×	0.005	GATA4
cardiac ventricle morphogenesis	1	624.1×	0.005	GATA4
embryonic foregut morphogenesis	1	561.7×	0.005	GATA4
atrioventricular canal development	1	510.7×	0.005	GATA4
intestinal epithelial cell differentiation	1	510.7×	0.005	GATA4
endocardial cushion development	1	468.1×	0.005	GATA4
cardiac right ventricle morphogenesis	1	468.1×	0.005	GATA4
cellular response to UV-A	1	468.1×	0.005	CERS1
atrial septum morphogenesis	1	432.1×	0.006	GATA4
negative regulation of D-glucose import across plasma membrane	1	401.2×	0.006	CERS1
negative regulation of cardiac muscle hypertrophy	1	374.5×	0.006	CERS1
regulation of cardiac muscle cell contraction	1	374.5×	0.006	GATA4
positive regulation of mitophagy	1	374.5×	0.006	CERS1
response to vitamin A	1	351.1×	0.006	GATA4
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1	312.1×	0.006	GATA4
endoderm development	1	208.1×	0.009	GATA4
negative regulation of apoptotic signaling pathway	1	187.2×	0.010	GATA4

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Tadalafil	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acetylcysteine.

Drug target analysis

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

Druggability breadth: 3 of 3 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
CERS1	0	0
MACROD2	0	0
GATA4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GATA4	5	Binding:5
MACROD2	4	Binding:2, Toxicity:2
CERS1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CERS1	2.3.1.299	sphingoid base N-stearoyltransferase
MACROD2	3.1.1.106	O-acetyl-ADP-ribose deacetylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	MACROD2
D	Druggable family + AlphaFold only, no drug	1	CERS1
E	Difficult family or no structure, no drug	1	GATA4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CERS1	2	—
MACROD2	4	—
GATA4	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 32.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	24
PHASE3	3
PHASE2	2
PHASE4	1
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00703352	PHASE4	COMPLETED	Eplerenone in Systemic Right Ventricle
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00006183	PHASE3	COMPLETED	Comparison of Hematocrit Levels in Infant Heart Surgery
NCT03661385	PHASE3	COMPLETED	Nitric Oxide During Bypass for Arterial Switch Operation
NCT00199771	PHASE2	COMPLETED	Hypertonic Saline Dextran in Pediatric Cardiac Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00513240	PHASE1/PHASE2	COMPLETED	Erythropoetin Neuroprotection for Neonatal Cardiac Surgery
NCT01915277	PHASE1	COMPLETED	A Phase I Study of Dexmedetomidine Bolus and Infusion in Corrective Infant Cardiac Surgery: Safety and Pharmacokinetics
NCT02588989	Not specified	ACTIVE_NOT_RECRUITING	Fibrosis, Valvular and Ventricular Function in Patients With TGA
NCT04106479	Not specified	RECRUITING	NIRS in Congenital Heart Defects - Correlation With Echocardiography
NCT04288596	Not specified	NOT_YET_RECRUITING	Canadian Adult Congenital Heart Disease Intervention Registry
NCT04335448	Not specified	ACTIVE_NOT_RECRUITING	Comprehensive Long-term Follow up of Adults With Arterial Switch Operation
NCT05452720	Not specified	RECRUITING	MASA Valve Early Feasibility Study
NCT05524324	Not specified	RECRUITING	Cardiac Resynchronization Therapy in Adult Congenital Heart Disease With Systemic Right Ventricle: RIGHT-CRT
NCT05809310	Not specified	RECRUITING	Effects Branch PA Stenting d-TGA, ToF and TA
NCT06768008	Not specified	RECRUITING	An Integrated Prenatal and Postnatal Treatment Model for the Treatment of Newborns With Critical Congenital Heart Disease
NCT06932081	Not specified	RECRUITING	Adult Congenital Heart Disease International EValuation of the Effectiveness of SGLT2i Registry
NCT00005190	Not specified	COMPLETED	Reproduction and Survival After Cardiac Defect Repair
NCT00837603	Not specified	COMPLETED	Physical Training in Transposition of the Great Arteries
NCT01916499	Not specified	COMPLETED	MRI Study After Arterial Switch Operation in Patients With Transposition of the Great Arteries
NCT02161471	Not specified	COMPLETED	Haemodynamics and Function of the Atria in Congenital Heart Disease by Cardiovascular Magnetic Resonance
NCT02184169	Not specified	COMPLETED	Oxygen Consumption-based Assessments of Hemodynamics in Neonates Following Congenital Heart Surgery (Oxy-CAHN Study)
NCT02415491	Not specified	UNKNOWN	Cardiovascular MRI and Cardiopulmonary Exercise Capacity After Neonatal ASO) in Young Adults
NCT03078413	Not specified	COMPLETED	Late Function After Surgery for Transposition of the Great Arteries
NCT03469843	Not specified	COMPLETED	Characterization of the Cardiac Reinnervation of Patients With Transposition of the Great Arteries Long After Repair With the Arterial Switch Operation. Correlation With Electrocardiographic and Exercise Test Parameters
NCT03833843	Not specified	COMPLETED	Sudden Cardiac Death in Systemic Right Ventricle
NCT04452188	Not specified	COMPLETED	Targeting Normoxia in Neonates With Cyanotic Congenital Heart Disease in the Intra-operative and Immediate Post-operative Period
NCT04616222	Not specified	UNKNOWN	A Retrospective Comparison of the Efficacy and Safety of Celsior® in Pediatric Cardiac Surgery for Transposition of the Great Vessels
NCT04788082	Not specified	WITHDRAWN	Clinical Impact of Rapid Prototyping 3D Models for Surgical Management
NCT05089773	Not specified	COMPLETED	Outcomes of Transposition of the Great Arteries After Arterial Switch Operation
NCT05160116	Not specified	COMPLETED	Influence of Timing of Switch Operation in Transposition of Great Arteries
NCT06258083	Not specified	COMPLETED	Systemic Right Ventricle Long-term Outcome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EPLERENONE	4	1
NITRIC OXIDE	4	1
CHEMBL5435500	0	1