Double outlet right ventricle

Summary

Double outlet right ventricle (MONDO:0018089) is a disease (an umbrella term covering 5 Mondo subtypes) with 4 cohort genes and 6 clinical trials. Top therapeutic interventions include propranolol.

At a glance

• Prevalence: 1-5 / 10 000 (Germany) [Orphanet-validated]
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 7
• Phenotypes (HPO): 28
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-5 / 10 000	10	Germany	Validated
Point prevalence	1-5 / 10 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0001719	Double outlet right ventricle	Obligate (100%)
HP:0000961	Cyanosis	Very frequent (80-99%)
HP:0000160	Narrow mouth	Frequent (30-79%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000176	Submucous cleft hard palate	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001629	Ventricular septal defect	Frequent (30-79%)
HP:0001642	Pulmonic stenosis	Frequent (30-79%)
HP:0001649	Tachycardia	Frequent (30-79%)
HP:0002789	Tachypnea	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004383	Hypoplastic left heart	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0030148	Heart murmur	Frequent (30-79%)
HP:0045025	Narrow palpebral fissure	Frequent (30-79%)
HP:3000022	Abnormality of cartilage of external ear	Frequent (30-79%)
HP:0000829	Hypoparathyroidism	Occasional (5-29%)
HP:0001636	Tetralogy of Fallot	Occasional (5-29%)
HP:0001660	Truncus arteriosus	Occasional (5-29%)
HP:0001680	Coarctation of aorta	Occasional (5-29%)
HP:0002566	Intestinal malrotation	Occasional (5-29%)
HP:0002901	Hypocalcemia	Occasional (5-29%)
HP:0004935	Pulmonary artery atresia	Occasional (5-29%)
HP:0010515	Aplasia/Hypoplasia of the thymus	Occasional (5-29%)
HP:0030853	Heterotaxy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	double outlet right ventricle
Mondo ID	MONDO:0018089
MeSH	D004310
Orphanet	3426
DOID	DOID:6406
ICD-10-CM	Q20.1
ICD-11	141717788
NCIT	C98916
SNOMED CT	204299009
UMLS	C0013069
MedGen	41649
GARD	0001908
MedDRA	10013611
Is cancer (heuristic)	no

Also known as: DORV · double outlet right ventricle

Data availability: 7 ClinVar variants.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › congenital heart disease › heart septal defect › ventricular septal defect › double outlet right ventricle

Related subtypes (4): ventricular septal defect 1, ventricular septal defect 2, ventricular septal defect 3, anterior deviation infundibular septum

Subtypes (5): double outlet right ventricle with subaortic or doubly committed ventricular septal defect, double outlet right ventricle with atrioventricular septal defect, pulmonary stenosis, heterotaxy, double outlet right ventricle with subaortic or doubly committed ventricular septal defect with pulmonary stenosis, double outlet right ventricle with subpulmonary ventricular septal defect, double outlet right ventricle with non-committed subpulmonary ventricular septal defect

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

7 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
39519	NM_012082.4(ZFPM2):c.2209A>G (p.Lys737Glu)	LOC126860469	Pathogenic	no assertion criteria provided
39517	NM_012082.4(ZFPM2):c.681T>G (p.Ile227Met)	ZFPM2	Pathogenic	no assertion criteria provided
6130	NM_012082.4(ZFPM2):c.2107A>C (p.Met703Leu)	ZFPM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
6748	NM_001492.6(GDF1):c.800G>A (p.Cys267Tyr)	CERS1	Uncertain significance	criteria provided, single submitter
523483	NM_005378.6(MYCN):c.1226C>T (p.Pro409Leu)	MYCN	Uncertain significance	criteria provided, multiple submitters, no conflicts
410969	NM_004387.4(NKX2-5):c.865AAC[2] (p.Asn291del)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
6128	NM_012082.4(ZFPM2):c.89A>G (p.Glu30Gly)	ZFPM2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 19 · 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
ZFPM2	Orphanet:2140	Congenital diaphragmatic hernia
ZFPM2	Orphanet:251510	46,XY partial gonadal dysgenesis
ZFPM2	Orphanet:3303	Tetralogy of Fallot
NKX2-5	Orphanet:101351	Familial isolated congenital asplenia
NKX2-5	Orphanet:1479	Atrial septal defect-atrioventricular conduction defects syndrome
NKX2-5	Orphanet:1627	Deletion 5q35 syndrome
NKX2-5	Orphanet:2248	Hypoplastic left heart syndrome
NKX2-5	Orphanet:3303	Tetralogy of Fallot
NKX2-5	Orphanet:334	Hereditary atrial fibrillation
NKX2-5	Orphanet:402075	Familial bicuspid aortic valve
NKX2-5	Orphanet:871	Hereditary progressive cardiac conduction defect
NKX2-5	Orphanet:95712	Thyroid ectopia
NKX2-5	Orphanet:95713	Athyreosis
NKX2-5	Orphanet:99103	Atrial septal defect, ostium secundum type
MYCN	Orphanet:357027	Hereditary retinoblastoma
MYCN	Orphanet:357034	Non-hereditary retinoblastoma
MYCN	Orphanet:391641	Feingold syndrome type 1
MYCN	Orphanet:635	Neuroblastoma

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CERS1	HGNC:14253	ENSG00000223802	P27544	Ceramide synthase 1	clinvar
ZFPM2	HGNC:16700	ENSG00000169946	Q8WW38	Zinc finger protein ZFPM2	clinvar
NKX2-5	HGNC:2488	ENSG00000183072	P52952	Homeobox protein Nkx-2.5	clinvar
MYCN	HGNC:7559	ENSG00000134323	P04198	N-myc proto-oncogene protein	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).
ZFPM2	Zinc finger protein ZFPM2	Transcription regulator that plays a central role in heart morphogenesis and development of coronary vessels from epicardium, by regulating genes that are essential during cardiogenesis.
NKX2-5	Homeobox protein Nkx-2.5	Transcription factor required for the development of the heart and the spleen.
MYCN	N-myc proto-oncogene protein	Positively regulates the transcription of MYCNOS in neuroblastoma cells.

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 0 · Druggable fraction: 0.25

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	3	6.2×	0.013
Enzyme (other)	1	3.0×	0.294

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CERS1	Enzyme (other)	yes	2.3.1.299	TLC-dom, Lag1/Lac1-like
ZFPM2	Transcription factor	no		Znf_C2H2_type, Znf_CCHC_FOG, Znf_C2H2_sf
NKX2-5	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
MYCN	Transcription factor	no		Tscrpt_reg_Myc, bHLH_dom, Tscrpt_reg_Myc_N

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
right frontal lobe	1
spinal cord	1
biceps brachii	1
germinal epithelium of ovary	1
skeletal muscle tissue of biceps brachii	1
apex of heart	1
cardiac atrium	1
right atrium auricular region	1
cortical plate	1
embryo	1
ventricular zone	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
ZFPM2	239	ubiquitous	marker	skeletal muscle tissue of biceps brachii, germinal epithelium of ovary, biceps brachii
NKX2-5	98	broad	yes	apex of heart, right atrium auricular region, cardiac atrium
MYCN	223	broad	yes	ventricular zone, cortical plate, embryo

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYCN	7,345
NKX2-5	2,355
ZFPM2	1,437
CERS1	76

Intra-cohort edges

A	B	Sources
NKX2-5	ZFPM2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NKX2-5	P52952	4
MYCN	P04198	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CERS1	P27544	88.95
ZFPM2	Q8WW38	51.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of CDH1 mRNA translation by microRNAs	1	259.6×	0.019	MYCN
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	190.3×	0.019	NKX2-5
Transcriptional regulation of testis differentiation	1	178.4×	0.019	ZFPM2
Physiological factors	1	167.9×	0.019	NKX2-5
Signaling by ALK	1	142.8×	0.019	MYCN
TGFBR3 expression	1	114.2×	0.019	MYCN
Cardiogenesis	1	105.7×	0.019	NKX2-5
Signaling by TGFBR3	1	92.1×	0.019	MYCN
Sphingolipid de novo biosynthesis	1	71.4×	0.022	CERS1
Signaling by TGFB family members	1	28.8×	0.046	MYCN
Regulation of PD-L1(CD274) transcription	1	27.2×	0.046	MYCN
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.069	ZFPM2
Signaling by Receptor Tyrosine Kinases	1	12.9×	0.081	MYCN
Signal Transduction	1	2.5×	0.339	MYCN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
right ventricular cardiac muscle tissue morphogenesis	2	4213.0×	4e-06	ZFPM2, NKX2-5
outflow tract septum morphogenesis	2	324.1×	7e-04	ZFPM2, NKX2-5
ventricular septum morphogenesis	2	216.1×	0.001	ZFPM2, NKX2-5
epithelial cell proliferation	2	156.0×	0.001	NKX2-5, MYCN
vasculogenesis	2	127.7×	0.002	ZFPM2, NKX2-5
positive regulation of epithelial cell proliferation	2	122.1×	0.002	NKX2-5, MYCN
lung development	2	99.1×	0.002	ZFPM2, MYCN
Purkinje myocyte differentiation	1	4213.0×	0.002	NKX2-5
septum secundum development	1	4213.0×	0.002	NKX2-5
cellular response to dithiothreitol	1	4213.0×	0.002	CERS1
cellular response to mycotoxin	1	2106.5×	0.004	CERS1
atrioventricular node cell fate commitment	1	2106.5×	0.004	NKX2-5
cardiac ventricle formation	1	1404.3×	0.004	NKX2-5
apoptotic process involved in heart morphogenesis	1	1404.3×	0.004	NKX2-5
proepicardium development	1	1404.3×	0.004	NKX2-5
pulmonary myocardium development	1	1404.3×	0.004	NKX2-5
regulation of inner ear auditory receptor cell differentiation	1	1404.3×	0.004	MYCN
ventricular cardiac myofibril assembly	1	1404.3×	0.004	NKX2-5
atrial cardiac muscle cell development	1	1404.3×	0.004	NKX2-5
bundle of His development	1	1053.2×	0.004	NKX2-5
atrial cardiac muscle tissue development	1	1053.2×	0.004	NKX2-5
positive regulation of cardioblast differentiation	1	1053.2×	0.004	NKX2-5
atrioventricular node cell development	1	1053.2×	0.004	NKX2-5
negative regulation of female gonad development	1	1053.2×	0.004	ZFPM2
heart development	2	39.4×	0.004	ZFPM2, NKX2-5
regulation of cardiac muscle cell proliferation	1	842.6×	0.004	NKX2-5
positive regulation of transcription by RNA polymerase II	3	11.2×	0.004	ZFPM2, NKX2-5, MYCN
atrioventricular node development	1	702.2×	0.005	NKX2-5
embryonic heart tube left/right pattern formation	1	702.2×	0.005	NKX2-5
autosome genomic imprinting	1	601.9×	0.005	MYCN

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
ZFPM2	0	0
NKX2-5	0	0
MYCN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MYCN	11	Binding:11
CERS1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CERS1	2.3.1.299	sphingoid base N-stearoyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	CERS1
E	Difficult family or no structure, no drug	3	ZFPM2, NKX2-5, MYCN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CERS1	2	—
ZFPM2	0	—
NKX2-5	0	—
MYCN	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04467671	PHASE2	RECRUITING	Two-Year Study of the Safety and Efficacy of the Second-Generation Tissue Engineered Vascular Grafts
NCT04713657	PHASE1	RECRUITING	Beta-blocker Administration for Cardiomyocyte Division
NCT06822400	Not specified	RECRUITING	Investigation of Tetralogy of Fallot in Neonates
NCT00497705	Not specified	COMPLETED	Genes Causing Ebstein’s Anomaly
NCT00972608	Not specified	COMPLETED	Surgical Planning for Reconstruction of Complex Heart Defects
NCT04788082	Not specified	WITHDRAWN	Clinical Impact of Rapid Prototyping 3D Models for Surgical Management

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PROPRANOLOL	4	1