Dextro-looped transposition of the great arteries

Summary

Dextro-looped transposition of the great arteries (MONDO:0019443) is a disease with 3 cohort genes.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 949
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-5 / 10 000	25	Worldwide	Validated
Prevalence at birth	1-5 / 10 000	24.25	Europe	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0000961	Cyanosis	Very frequent (80-99%)
HP:0001649	Tachycardia	Very frequent (80-99%)
HP:0001693	Cardiac shunt	Very frequent (80-99%)
HP:0011028	Abnormality of blood circulation	Very frequent (80-99%)
HP:0011563	Abnormal ventriculoarterial connection	Very frequent (80-99%)
HP:0012418	Hypoxemia	Very frequent (80-99%)
HP:0030148	Heart murmur	Very frequent (80-99%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001629	Ventricular septal defect	Frequent (30-79%)
HP:0001631	Atrial septal defect	Frequent (30-79%)
HP:0001633	Abnormal mitral valve morphology	Frequent (30-79%)
HP:0001635	Congestive heart failure	Frequent (30-79%)
HP:0001640	Cardiomegaly	Frequent (30-79%)
HP:0001641	Abnormal pulmonary valve morphology	Frequent (30-79%)
HP:0001643	Patent ductus arteriosus	Frequent (30-79%)
HP:0001667	Right ventricular hypertrophy	Frequent (30-79%)
HP:0002789	Tachypnea	Frequent (30-79%)
HP:0006704	Abnormal coronary artery morphology	Frequent (30-79%)
HP:0010772	Anomalous pulmonary venous return	Frequent (30-79%)
HP:0012303	Abnormal aortic arch morphology	Frequent (30-79%)
HP:0025074	Abnormal QRS complex	Frequent (30-79%)
HP:0031348	Dextrotransposition of the great arteries	Frequent (30-79%)
HP:0031349	Levotransposition of the great arteries	Frequent (30-79%)
HP:0032092	Left ventricular outflow tract obstruction	Frequent (30-79%)
HP:0200128	Biventricular hypertrophy	Frequent (30-79%)
HP:0001518	Small for gestational age	Occasional (5-29%)
HP:0001680	Coarctation of aorta	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0011611	Interrupted aortic arch	Occasional (5-29%)
HP:0012304	Hypoplastic aortic arch	Occasional (5-29%)
HP:0009800	Maternal diabetes	Very rare (<1-4%)
HP:0011438	Maternal teratogenic exposure	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dextro-looped transposition of the great arteries
Mondo ID	MONDO:0019443
OMIM	608808
Orphanet	860
DOID	DOID:0060770
UMLS	C3531771
MedGen	758887
GARD	0005476
Is cancer (heuristic)	no

Also known as: congenitally uncorrected transposition of the great arteries · congenitally uncorrected transposition of the great vessels · DTGA · isolated ventriculoarterial discordance · ventriculoarterial discordance with atrioventricular concordance

Data availability: 949 ClinVar variants.

Disease family

An umbrella term covering 4 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 › dextro-looped transposition of the great arteries

Related subtypes (2): heterotaxy, visceral, 2, autosomal, congenitally corrected transposition of the great arteries

Subtypes (4): congenital heart defects, multiple types, 6, isolated congenitally uncorrected transposition of the great arteries, congenitally uncorrected transposition of the great arteries with cardiac malformation, congenitally uncorrected transposition of the great arteries with coarctation

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

600 retrieved; paginated sample, class counts are floors:

287 likely benign, 137 uncertain significance, 73 benign, 49 conflicting classifications of pathogenicity, 33 benign/likely benign, 18 pathogenic, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1174607	NM_004302.5(ACVR1B):c.912G>A (p.Met304Ile)	ACVR1B	Pathogenic	no assertion criteria provided
1703210	NM_001200.4(BMP2):c.962A>T (p.His321Leu)	BMP2	Pathogenic	no assertion criteria provided
1064782	NM_015335.5(MED13L):c.2071C>T (p.Gln691Ter)	MED13L	Pathogenic	criteria provided, multiple submitters, no conflicts
1071342	NM_015335.5(MED13L):c.1405dup (p.Thr469fs)	MED13L	Pathogenic	criteria provided, single submitter
1942153	NM_015335.5(MED13L):c.475A>T (p.Lys159Ter)	MED13L	Pathogenic	criteria provided, single submitter
2007805	NM_015335.5(MED13L):c.6239dup (p.Leu2081fs)	MED13L	Pathogenic	criteria provided, single submitter
2035565	NM_015335.5(MED13L):c.3381del (p.Phe1128fs)	MED13L	Pathogenic	criteria provided, single submitter
2105567	NM_015335.5(MED13L):c.5766_5769del (p.Thr1923fs)	MED13L	Pathogenic	criteria provided, single submitter
224153	NM_015335.5(MED13L):c.6485C>T (p.Thr2162Met)	MED13L	Pathogenic	criteria provided, multiple submitters, no conflicts
2426138	NC_000012.11:g.(?116418535)(116420428_?)del	MED13L	Pathogenic	criteria provided, single submitter
2426139	NC_000012.11:g.(?116534454)(116549337_?)del	MED13L	Pathogenic	criteria provided, single submitter
2579461	NM_015335.5(MED13L):c.6280C>T (p.Pro2094Ser)	MED13L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2700544	NM_015335.5(MED13L):c.5818del (p.Ala1940fs)	MED13L	Pathogenic	criteria provided, single submitter
2761587	NM_015335.5(MED13L):c.4715del (p.Asn1572fs)	MED13L	Pathogenic	criteria provided, single submitter
2800293	NM_015335.5(MED13L):c.3779del (p.Ser1260fs)	MED13L	Pathogenic	criteria provided, single submitter
2820850	NM_015335.5(MED13L):c.1486G>T (p.Glu496Ter)	MED13L	Pathogenic	criteria provided, single submitter
2842211	NM_015335.5(MED13L):c.2110C>T (p.Gln704Ter)	MED13L	Pathogenic	criteria provided, single submitter
3244300	NC_000012.11:g.(?116440808)(116440907_?)del	MED13L	Pathogenic	criteria provided, single submitter
3244301	NC_000012.11:g.(?116534474)(116675510_?)del	MED13L	Pathogenic	criteria provided, single submitter
2762830	NM_015335.5(MED13L):c.4955+1G>A	MED13L	Likely pathogenic	criteria provided, single submitter
2780258	NM_015335.5(MED13L):c.5175+1G>A	MED13L	Likely pathogenic	criteria provided, single submitter
1003426	NM_015335.5(MED13L):c.2350C>T (p.Arg784Trp)	MED13L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003545	NM_015335.5(MED13L):c.1185A>C (p.Gln395His)	MED13L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1015642	NM_015335.5(MED13L):c.6347C>T (p.Ser2116Leu)	MED13L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1040460	NM_015335.5(MED13L):c.2117G>A (p.Gly706Glu)	MED13L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043776	NM_015335.5(MED13L):c.2019A>T (p.Leu673Phe)	MED13L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1062651	NM_015335.5(MED13L):c.5471A>G (p.Asn1824Ser)	MED13L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1098589	NM_015335.5(MED13L):c.2075C>G (p.Pro692Arg)	MED13L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1125903	NM_015335.5(MED13L):c.1724C>T (p.Ser575Leu)	MED13L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1214164	NM_015335.5(MED13L):c.3068C>T (p.Thr1023Met)	MED13L	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BMP2	Orphanet:261295	20p12.3 microdeletion syndrome
BMP2	Orphanet:93396	Brachydactyly type A2
MED13L	Orphanet:216718	Isolated congenitally uncorrected transposition of the great arteries
MED13L	Orphanet:369891	Developmental delay-facial dysmorphism syndrome due to MED13L deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BMP2	HGNC:1069	ENSG00000125845	P12643	Bone morphogenetic protein 2	clinvar
ACVR1B	HGNC:172	ENSG00000135503	P36896	Activin receptor type-1B	clinvar
MED13L	HGNC:22962	ENSG00000123066	Q71F56	Mediator of RNA polymerase II transcription subunit 13-like	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
ACVR1B	Activin receptor type-1B	Transmembrane serine/threonine kinase activin type-1 receptor forming an activin receptor complex with activin receptor type-2 (ACVR2A or ACVR2B).
MED13L	Mediator of RNA polymerase II transcription subunit 13-like	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BMP2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
ACVR1B	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
MED13L	Other/Unknown	no		Med13_C, Mediator_Med13_N, MID_MedPIWI

Expression context

Cohort genes with no expression data: 0.

3 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
cartilage tissue	1
pancreatic ductal cell	1
pigmented layer of retina	1
middle temporal gyrus	1
oocyte	1
secondary oocyte	1
calcaneal tendon	1
colonic epithelium	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BMP2	238	broad	marker	cartilage tissue, pancreatic ductal cell, pigmented layer of retina
ACVR1B	296	ubiquitous	marker	secondary oocyte, oocyte, middle temporal gyrus
MED13L	297	ubiquitous	marker	calcaneal tendon, colonic epithelium, tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BMP2	3,131
ACVR1B	2,433
MED13L	1,606

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BMP2	P12643	21
ACVR1B	P36896	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MED13L	Q71F56	56.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 3 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
Signaling by TGFB family members	2	76.9×	0.006	BMP2, ACVR1B
Regulation of signaling by NODAL	1	317.2×	0.034	ACVR1B
Signaling by Activin	1	253.8×	0.034	ACVR1B
Signaling by NODAL	1	165.5×	0.036	ACVR1B
Signaling by BMP	1	119.0×	0.036	BMP2
Elastic fibre formation	1	112.0×	0.036	BMP2
Molecules associated with elastic fibres	1	102.9×	0.036	BMP2
Transcriptional regulation by RUNX2	1	84.6×	0.038	BMP2
Respiratory Syncytial Virus Infection Pathway	1	65.6×	0.038	MED13L
Regulation of RUNX2 expression and activity	1	60.4×	0.038	BMP2
RSV-host interactions	1	52.1×	0.038	MED13L
Adipogenesis	1	52.1×	0.038	MED13L
Developmental Biology	2	9.6×	0.038	ACVR1B, MED13L
Regulation of lipid metabolism by PPARalpha	1	47.0×	0.039	MED13L
Transcriptional regulation of white adipocyte differentiation	1	43.3×	0.040	MED13L
Signal Transduction	2	6.8×	0.044	BMP2, ACVR1B
PPARA activates gene expression	1	31.5×	0.048	MED13L
Extracellular matrix organization	1	21.0×	0.068	BMP2
Metabolism of lipids	1	10.5×	0.123	MED13L
Viral Infection Pathways	1	10.3×	0.123	MED13L
Infectious disease	1	8.3×	0.144	MED13L
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
Disease	1	4.4×	0.221	MED13L
Metabolism	1	3.9×	0.237	MED13L

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
negative regulation of calcium-independent cell-cell adhesion	1	5617.3×	0.005	BMP2
endodermal-mesodermal cell signaling	1	2808.7×	0.005	BMP2
cardiac atrium formation	1	2808.7×	0.005	BMP2
cardiocyte differentiation	1	2808.7×	0.005	BMP2
mesenchymal cell proliferation involved in ureteric bud development	1	2808.7×	0.005	BMP2
positive regulation of extracellular matrix constituent secretion	1	1872.4×	0.005	BMP2
embryonic heart tube anterior/posterior pattern specification	1	1872.4×	0.005	BMP2
corticotropin hormone secreting cell differentiation	1	1872.4×	0.005	BMP2
positive regulation of bone mineralization involved in bone maturation	1	1872.4×	0.005	BMP2
cardiac jelly development	1	1872.4×	0.005	BMP2
positive regulation of phosphatase activity	1	1404.3×	0.005	BMP2
negative regulation of aldosterone biosynthetic process	1	1404.3×	0.005	BMP2
atrioventricular canal morphogenesis	1	1404.3×	0.005	BMP2
negative regulation of cortisol biosynthetic process	1	1404.3×	0.005	BMP2
in utero embryonic development	2	48.0×	0.005	BMP2, ACVR1B
negative regulation of gene expression	2	46.0×	0.005	BMP2, ACVR1B
aortic valve development	1	1123.5×	0.005	BMP2
negative regulation of steroid biosynthetic process	1	1123.5×	0.005	BMP2
positive regulation of odontogenesis	1	1123.5×	0.005	BMP2
telencephalon regionalization	1	936.2×	0.005	BMP2
positive regulation of activin receptor signaling pathway	1	936.2×	0.005	ACVR1B
thyroid-stimulating hormone-secreting cell differentiation	1	936.2×	0.005	BMP2
regulation of odontogenesis of dentin-containing tooth	1	802.5×	0.005	BMP2
mesenchyme development	1	802.5×	0.005	BMP2
positive regulation of trophoblast cell migration	1	802.5×	0.005	ACVR1B
positive regulation of odontoblast differentiation	1	802.5×	0.005	BMP2
negative regulation of cardiac muscle cell differentiation	1	802.5×	0.005	BMP2
heart induction	1	702.2×	0.005	BMP2
ameloblast differentiation	1	702.2×	0.005	BMP2
negative regulation of insulin-like growth factor receptor signaling pathway	1	702.2×	0.005	BMP2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ACVR1B	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACVR1B	21	4
BMP2	0	0
MED13L	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	ACVR1B
DABRAFENIB	4	ACVR1B
NINTEDANIB	4	ACVR1B
DASATINIB	4	ACVR1B
CRIZOTINIB	4	ACVR1B
SARACATINIB	3	ACVR1B
CEDIRANIB	3	ACVR1B
LESTAURTINIB	3	ACVR1B
DORAMAPIMOD	2	ACVR1B
GALUNISERTIB	2	ACVR1B
OSI-632	2	ACVR1B
OSI-027	2	ACVR1B
VACTOSERTIB	2	ACVR1B
DANUSERTIB	2	ACVR1B
R-406	2	ACVR1B
AT-9283	2	ACVR1B
KER-047	2	ACVR1B
GSK-1070916	1	ACVR1B
MK-5108	1	ACVR1B
CYC-116	1	ACVR1B
PF-06952229	1	ACVR1B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ACVR1B	286	Binding:282, ADMET:3, Functional:1
BMP2	22	Binding:18, Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACVR1B	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ACVR1B	286

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

21 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.

Compound	Max phase	Cohort target (bioactivity)
FEDRATINIB	4	ACVR1B
DABRAFENIB	4	ACVR1B
NINTEDANIB	4	ACVR1B
DASATINIB	4	ACVR1B
CRIZOTINIB	4	ACVR1B
SARACATINIB	3	ACVR1B
CEDIRANIB	3	ACVR1B
LESTAURTINIB	3	ACVR1B
DORAMAPIMOD	2	ACVR1B
GALUNISERTIB	2	ACVR1B
OSI-632	2	ACVR1B
OSI-027	2	ACVR1B
VACTOSERTIB	2	ACVR1B
DANUSERTIB	2	ACVR1B
R-406	2	ACVR1B
AT-9283	2	ACVR1B
KER-047	2	ACVR1B
GSK-1070916	1	ACVR1B
MK-5108	1	ACVR1B
CYC-116	1	ACVR1B
PF-06952229	1	ACVR1B

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ACVR1B
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	2	BMP2, MED13L

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BMP2	22	—
MED13L	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.