Congenitally corrected transposition of the great arteries

Summary

Congenitally corrected transposition of the great arteries (MONDO:0016301) is a disease with 1 cohort gene and 3 clinical trials.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 49
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	3	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

49 HPO clinical features (Orphanet curated; top 49 by frequency):

HPO ID	Term	Frequency
HP:0001627	Abnormal heart morphology	Very frequent (80-99%)
HP:0001629	Ventricular septal defect	Very frequent (80-99%)
HP:0001702	Abnormal tricuspid valve morphology	Very frequent (80-99%)
HP:0006705	Abnormal atrioventricular valve morphology	Very frequent (80-99%)
HP:0011103	Abnormal left ventricular outflow tract morphology	Very frequent (80-99%)
HP:0011553	Discordant atrioventricular connection	Very frequent (80-99%)
HP:0001631	Atrial septal defect	Frequent (30-79%)
HP:0001642	Pulmonic stenosis	Frequent (30-79%)
HP:0001662	Bradycardia	Frequent (30-79%)
HP:0005150	Abnormal atrioventricular conduction	Frequent (30-79%)
HP:0011539	Atrial situs ambiguous	Frequent (30-79%)
HP:0011552	Ambiguous atrioventricular connection	Frequent (30-79%)
HP:0030148	Heart murmur	Frequent (30-79%)
HP:0031546	Cardiac conduction abnormality	Frequent (30-79%)
HP:0000961	Cyanosis	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001651	Dextrocardia	Occasional (5-29%)
HP:0001659	Aortic regurgitation	Occasional (5-29%)
HP:0001696	Situs inversus totalis	Occasional (5-29%)
HP:0001709	Third degree atrioventricular block	Occasional (5-29%)
HP:0001716	Wolff-Parkinson-White syndrome	Occasional (5-29%)
HP:0001750	Single ventricle	Occasional (5-29%)
HP:0003388	Easy fatigability	Occasional (5-29%)
HP:0004755	Supraventricular tachycardia	Occasional (5-29%)
HP:0004935	Pulmonary artery atresia	Occasional (5-29%)
HP:0005180	Tricuspid regurgitation	Occasional (5-29%)
HP:0005185	Global systolic dysfunction	Occasional (5-29%)
HP:0006699	Premature atrial contractions	Occasional (5-29%)
HP:0010316	Ebstein anomaly of the tricuspid valve	Occasional (5-29%)
HP:0011538	Atrial situs inversus	Occasional (5-29%)
HP:0011581	Double outlet left ventricle	Occasional (5-29%)
HP:0011590	Double aortic arch	Occasional (5-29%)
HP:0011621	Gerbode ventricular septal defect	Occasional (5-29%)
HP:0011663	Right ventricular cardiomyopathy	Occasional (5-29%)
HP:0011667	Bilateral superior vena cava with bridging vein	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0011682	Perimembranous ventricular septal defect	Occasional (5-29%)
HP:0011688	Supraventricular tachycardia with an accessory connection mediated pathway	Occasional (5-29%)
HP:0011704	Sick sinus syndrome	Occasional (5-29%)
HP:0011705	First degree atrioventricular block	Occasional (5-29%)
HP:0011707	Mobitz I atrioventricular block	Occasional (5-29%)
HP:0012537	Food intolerance	Occasional (5-29%)
HP:0012722	Heart block	Occasional (5-29%)
HP:0031567	Abnormal aortic valve cusp morphology	Occasional (5-29%)
HP:0004749	Atrial flutter	Very rare (<1-4%)
HP:0004756	Ventricular tachycardia	Very rare (<1-4%)
HP:0011599	Mesocardia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenitally corrected transposition of the great arteries
Mondo ID	MONDO:0016301
MeSH	D000080041
Orphanet	216694
ICD-11	254915185
NCIT	C98902
SNOMED CT	83799000
UMLS	C0344616
MedGen	87489
GARD	0001544
MedDRA	10011120
Is cancer (heuristic)	no

Also known as: congenitally corrected transposition of the great vessels · discordant ventriculoarterial and atrioventricular connections · Double discordance · L-transposition of the great arteries · L-transposition of the great vessels · levo-transposition of the great arteries · levo-transposition of the great vessels · transposition of the great arteries, congenitally corrected · transposition of the great vessels, congenitally corrected · ventricular inversion · ventriculoarterial and atrioventricular discordance

Data availability: 1 ClinVar variant.

Disease family

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 › congenitally corrected transposition of the great arteries

Related subtypes (2): heterotaxy, visceral, 2, autosomal, dextro-looped transposition of the great arteries

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

1 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
690399	NM_018055.5(NODAL):c.555dup (p.Thr186fs)	NODAL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NODAL	Orphanet:101063	Situs inversus totalis
NODAL	Orphanet:157769	Situs ambiguus
NODAL	Orphanet:220386	Semilobar holoprosencephaly
NODAL	Orphanet:280195	Septopreoptic holoprosencephaly
NODAL	Orphanet:280200	Microform holoprosencephaly
NODAL	Orphanet:93924	Lobar holoprosencephaly
NODAL	Orphanet:93925	Alobar holoprosencephaly
NODAL	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly

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
NODAL	HGNC:7865	ENSG00000156574	Q96S42	Nodal homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NODAL	Nodal homolog	Essential for mesoderm formation and axial patterning during embryonic development.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NODAL	Other/Unknown	no		TGF-b_C, TGF-beta-like, TGFb_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 muscle of right atrium	1
left ventricle myocardium	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NODAL	138	tissue_specific	marker	upper arm skin, cardiac muscle of right atrium, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NODAL	1,093

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NODAL	Q96S42	1

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
Regulation of signaling by NODAL	1	951.7×	0.002	NODAL
Signaling by NODAL	1	496.5×	0.002	NODAL

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
polarity specification of proximal/distal axis	1	16852.0×	7e-04	NODAL
floor plate morphogenesis	1	16852.0×	7e-04	NODAL
axial mesodermal cell fate specification	1	16852.0×	7e-04	NODAL
epiblast cell-extraembryonic ectoderm cell signaling	1	16852.0×	7e-04	NODAL
trophectodermal cellular morphogenesis	1	8426.0×	7e-04	NODAL
negative regulation of cell development	1	8426.0×	7e-04	NODAL
left lung morphogenesis	1	8426.0×	7e-04	NODAL
negative regulation of chorionic trophoblast cell proliferation	1	8426.0×	7e-04	NODAL
neural fold formation	1	4213.0×	0.001	NODAL
inhibition of neuroepithelial cell differentiation	1	4213.0×	0.001	NODAL
formation of anatomical boundary	1	4213.0×	0.001	NODAL
maternal process involved in parturition	1	3370.4×	0.001	NODAL
regulation of gastrulation	1	2808.7×	0.001	NODAL
negative regulation of trophoblast cell migration	1	2407.4×	0.001	NODAL
embryonic process involved in female pregnancy	1	2106.5×	0.001	NODAL
determination of left/right asymmetry in lateral mesoderm	1	1872.4×	0.001	NODAL
mesendoderm development	1	1872.4×	0.001	NODAL
maternal placenta development	1	1532.0×	0.002	NODAL
cell migration involved in gastrulation	1	1532.0×	0.002	NODAL
primitive streak formation	1	1404.3×	0.002	NODAL
regulation of stem cell population maintenance	1	1404.3×	0.002	NODAL
vasculature development	1	1123.5×	0.002	NODAL
nodal signaling pathway	1	1123.5×	0.002	NODAL
digestive tract morphogenesis	1	991.3×	0.002	NODAL
negative regulation of androgen receptor signaling pathway	1	936.2×	0.002	NODAL
embryonic placenta development	1	766.0×	0.002	NODAL
positive regulation of cell-cell adhesion	1	766.0×	0.002	NODAL
cell surface receptor protein serine/threonine kinase signaling pathway	1	732.7×	0.002	NODAL
embryonic cranial skeleton morphogenesis	1	581.1×	0.003	NODAL
embryonic pattern specification	1	543.6×	0.003	NODAL

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
NODAL	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	NODAL

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)
NODAL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05524324	Not specified	RECRUITING	Cardiac Resynchronization Therapy in Adult Congenital Heart Disease With Systemic Right Ventricle: RIGHT-CRT
NCT06932081	Not specified	RECRUITING	Adult Congenital Heart Disease International EValuation of the Effectiveness of SGLT2i Registry
NCT04788082	Not specified	WITHDRAWN	Clinical Impact of Rapid Prototyping 3D Models for Surgical Management