Congenital total pulmonary venous return anomaly

Summary

Congenital total pulmonary venous return anomaly (MONDO:0007130) is a disease with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 16
• Phenotypes (HPO): 40
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	9	Worldwide	Validated
Prevalence at birth	1-9 / 100 000	9	Worldwide	Validated
Point prevalence	1-9 / 100 000	8	United States	Validated
Prevalence at birth	1-9 / 100 000	8	United States	Validated

Signs & symptoms

Clinical features (HPO)

40 HPO clinical features (Orphanet curated; top 40 by frequency):

HPO ID	Term	Frequency
HP:0002098	Respiratory distress	Very frequent (80-99%)
HP:0000961	Cyanosis	Frequent (30-79%)
HP:0001631	Atrial septal defect	Frequent (30-79%)
HP:0001649	Tachycardia	Frequent (30-79%)
HP:0002092	Pulmonary arterial hypertension	Frequent (30-79%)
HP:0002875	Exertional dyspnea	Frequent (30-79%)
HP:0011539	Atrial situs ambiguous	Frequent (30-79%)
HP:0011719	Supracardiac total anomalous pulmonary venous connection	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0012763	Paroxysmal dyspnea	Frequent (30-79%)
HP:0000980	Pallor	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001640	Cardiomegaly	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001651	Dextrocardia	Occasional (5-29%)
HP:0001708	Right ventricular failure	Occasional (5-29%)
HP:0001719	Double outlet right ventricle	Occasional (5-29%)
HP:0001750	Single ventricle	Occasional (5-29%)
HP:0002033	Poor suck	Occasional (5-29%)
HP:0002089	Pulmonary hypoplasia	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0004383	Hypoplastic left heart	Occasional (5-29%)
HP:0004415	Pulmonary artery stenosis	Occasional (5-29%)
HP:0004887	Respiratory failure requiring assisted ventilation	Occasional (5-29%)
HP:0005180	Tricuspid regurgitation	Occasional (5-29%)
HP:0005253	Increased anterioposterior diameter of thorax	Occasional (5-29%)
HP:0005949	Apneic episodes in infancy	Occasional (5-29%)
HP:0009805	Low-output congestive heart failure	Occasional (5-29%)
HP:0011720	Cardiac total anomalous pulmonary venous connection	Occasional (5-29%)
HP:0011721	Infracardiac total anomalous pulmonary venous connection	Occasional (5-29%)
HP:0011722	Mixed total anomalous pulmonary venous connection	Occasional (5-29%)
HP:0030853	Heterotaxy	Occasional (5-29%)
HP:0030918	Low 1-minute APGAR score	Occasional (5-29%)
HP:0030919	Low 5-minute APGAR score	Occasional (5-29%)
HP:0001653	Mitral regurgitation	Very rare (<1-4%)
HP:0001669	Transposition of the great arteries	Very rare (<1-4%)
HP:0001680	Coarctation of aorta	Very rare (<1-4%)
HP:0011560	Mitral atresia	Very rare (<1-4%)
HP:0012304	Hypoplastic aortic arch	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital total pulmonary venous return anomaly
Mondo ID	MONDO:0007130
OMIM	106700
Orphanet	99125
DOID	DOID:4297
ICD-11	1532925990
NCIT	C98585
SNOMED CT	111323005
UMLS	C4551903
MedGen	1648157
GARD	0016896
Is cancer (heuristic)	no

Also known as: TAPVR · TAPVR1 · total anomalous pulmonary venous return · total anomalous pulmonary VENOUS return 1

Data availability: 16 ClinVar variants · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › congenital heart disease › congenital pulmonary veins anomaly › congenital pulmonary venous return anomaly › congenital total pulmonary venous return anomaly

Related subtypes (2): scimitar syndrome, congenital partial pulmonary venous return anomaly

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

16 retrieved; paginated sample, class counts are floors:

7 benign/likely benign, 5 benign, 2 conflicting classifications of pathogenicity, 1 uncertain significance, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
45636	NM_014391.3(ANKRD1):c.652-10A>T	ANKRD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
45639	NM_014391.3(ANKRD1):c.827C>T (p.Ala276Val)	ANKRD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
518231	NM_014391.3(ANKRD1):c.710A>G (p.His237Arg)	ANKRD1	Uncertain significance	criteria provided, single submitter
136401	NM_014391.3(ANKRD1):c.208-16C>T	ANKRD1	Benign	criteria provided, multiple submitters, no conflicts
136404	NM_014391.3(ANKRD1):c.-17A>G	ANKRD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
178005	NM_014391.3(ANKRD1):c.150C>G (p.Ala50=)	ANKRD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
201655	NM_014391.3(ANKRD1):c.346-19_346-18del	ANKRD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
201656	NM_014391.3(ANKRD1):c.346-15_346-14del	ANKRD1	Benign	criteria provided, multiple submitters, no conflicts
301605	NM_014391.3(ANKRD1):c.346-29_346-12del	ANKRD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
45625	NM_014391.3(ANKRD1):c.148G>C (p.Ala50Pro)	ANKRD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
45631	NM_014391.3(ANKRD1):c.346-17_346-10del	ANKRD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
45632	NM_014391.3(ANKRD1):c.346-19_346-14del	ANKRD1	Benign	criteria provided, multiple submitters, no conflicts
516096	NM_014391.3(ANKRD1):c.346-35_346-12del	ANKRD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
522238	NM_014391.3(ANKRD1):c.346-15_346-14insA	ANKRD1	Benign	criteria provided, single submitter
522240	NM_014391.3(ANKRD1):c.346-16_346-15insATA	ANKRD1	Likely benign	criteria provided, single submitter
771049	NM_001719.3(BMP7):c.962A>G (p.Asn321Ser)	BMP7	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANKRD1	Orphanet:154	Familial isolated dilated cardiomyopathy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BMP7	HGNC:1074	ENSG00000101144	P18075	Bone morphogenetic protein 7	clinvar
ANKRD1	HGNC:15819	ENSG00000148677	Q15327	Ankyrin repeat domain-containing protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BMP7	Bone morphogenetic protein 7	Growth factor of the TGF-beta superfamily that plays important role in various biological processes, including embryogenesis, hematopoiesis, neurogenesis and skeletal morphogenesis.
ANKRD1	Ankyrin repeat domain-containing protein 1	May play an important role in endothelial cell activation.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BMP7	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
ANKRD1	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
pigmented layer of retina	1
ventricular zone	1
apex of heart	1
cardiac atrium	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BMP7	243	broad	marker	pigmented layer of retina, ventricular zone, endometrium epithelium
ANKRD1	155	ubiquitous	marker	apex of heart, right atrium auricular region, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BMP7	3,134
ANKRD1	2,441

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BMP7	P18075	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKRD1	Q15327	82.64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 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
Transcriptional regulation of brown and beige adipocyte differentiation	1	571.0×	0.018	BMP7
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	1	190.3×	0.018	BMP7
Elastic fibre formation	1	167.9×	0.018	BMP7
Molecules associated with elastic fibres	1	154.3×	0.018	BMP7
Adipogenesis	1	78.2×	0.026	BMP7
Regulation of lipid metabolism by PPARalpha	1	70.5×	0.026	ANKRD1
PPARA activates gene expression	1	47.2×	0.033	ANKRD1
Extracellular matrix organization	1	31.6×	0.043	BMP7
Metabolism of lipids	1	15.8×	0.076	ANKRD1
Developmental Biology	1	7.2×	0.147	BMP7
Metabolism	1	5.8×	0.165	ANKRD1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of mesenchymal cell apoptotic process involved in nephron morphogenesis	1	8426.0×	0.002	BMP7
mesenchymal cell apoptotic process involved in nephron morphogenesis	1	8426.0×	0.002	BMP7
negative regulation of glomerular mesangial cell proliferation	1	4213.0×	0.002	BMP7
nephrogenic mesenchyme morphogenesis	1	4213.0×	0.002	BMP7
negative regulation of striated muscle cell apoptotic process	1	2808.7×	0.002	BMP7
neural fold elevation formation	1	2808.7×	0.002	BMP7
monocyte aggregation	1	2808.7×	0.002	BMP7
metanephric mesenchyme morphogenesis	1	2808.7×	0.002	BMP7
metanephric mesenchymal cell proliferation involved in metanephros development	1	2808.7×	0.002	BMP7
positive regulation of hyaluranon cable assembly	1	2808.7×	0.002	BMP7
positive regulation of cardiac neural crest cell migration involved in outflow tract morphogenesis	1	2808.7×	0.002	BMP7
cellular response to hypoxia	2	121.2×	0.002	BMP7, ANKRD1
positive regulation of apoptotic process	2	56.7×	0.002	BMP7, ANKRD1
negative regulation of prostatic bud formation	1	2106.5×	0.003	BMP7
allantois development	1	2106.5×	0.003	BMP7
regulation of branching involved in prostate gland morphogenesis	1	1685.2×	0.003	BMP7
phospholipase C/protein kinase C signal transduction	1	1404.3×	0.003	ANKRD1
regulation of removal of superoxide radicals	1	1404.3×	0.003	BMP7
negative regulation of mitotic nuclear division	1	1203.7×	0.003	BMP7
mesenchyme development	1	1203.7×	0.003	BMP7
pericardium morphogenesis	1	1053.2×	0.003	BMP7
ameloblast differentiation	1	1053.2×	0.003	BMP7
mesenchymal cell differentiation	1	1053.2×	0.003	BMP7
chorio-allantoic fusion	1	1053.2×	0.003	BMP7
positive regulation of epithelial cell differentiation	1	936.2×	0.003	BMP7
heart trabecula morphogenesis	1	936.2×	0.003	BMP7
negative regulation of DNA biosynthetic process	1	936.2×	0.003	ANKRD1
mesonephros development	1	766.0×	0.004	BMP7
embryonic skeletal joint morphogenesis	1	766.0×	0.004	BMP7
endocardial cushion formation	1	702.2×	0.004	BMP7

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
BMP7	0	0
ANKRD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	BMP7, ANKRD1

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)
BMP7	0	—
ANKRD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04452188	Not specified	COMPLETED	Targeting Normoxia in Neonates With Cyanotic Congenital Heart Disease in the Intra-operative and Immediate Post-operative Period