Congenital heart defects, multiple types, 4

Summary

Congenital heart defects, multiple types, 4 (MONDO:0014344) is a disease caused by NR2F2 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: NR2F2 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 91

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital heart defects, multiple types, 4
Mondo ID	MONDO:0014344
OMIM	615779
UMLS	C4014310
MedGen	862747
GARD	0024987
Is cancer (heuristic)	no

Also known as: CHTD4 · congenital heart defects, multiple types caused by mutation in NR2F2 · congenital heart defects, multiple types, 4 · NR2F2 congenital heart defects, multiple types

Data availability: 91 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › congenital heart disease › congenital heart defects, multiple types › congenital heart defects, multiple types, 4

Related subtypes (7): congenital heart defects, multiple types, 6, congenital heart defects, multiple types, 3, congenital heart defects, multiple types, 2, congenital heart defects, multiple types, 5, MYH-6 related congenital heart defects, congenital heart defects, multiple types, 8, with or without heterotaxy, congenital heart defects, multiple types, 9

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

91 retrieved; paginated sample, class counts are floors:

38 likely benign, 26 uncertain significance, 14 pathogenic, 6 likely pathogenic, 3 benign, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1702934	NM_001719.3(BMP7):c.523C>T (p.Arg175Trp)	BMP7	Pathogenic	no assertion criteria provided
2574123	NM_001077415.3(CRELD1):c.223T>C (p.Trp75Arg)	CRELD1	Pathogenic	no assertion criteria provided
2574125	NM_001077415.3(CRELD1):c.863G>T (p.Arg288Leu)	CRELD1	Pathogenic	no assertion criteria provided
128232	NM_021005.4(NR2F2):c.1022C>A (p.Ser341Tyr)	NR2F2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
128233	NM_021005.4(NR2F2):c.614A>T (p.Asn205Ile)	NR2F2	Pathogenic	no assertion criteria provided
128235	NM_021005.4(NR2F2):c.970+1G>A	NR2F2	Pathogenic	no assertion criteria provided
1452069	NM_021005.4(NR2F2):c.604C>T (p.Gln202Ter)	NR2F2	Pathogenic	criteria provided, single submitter
280543	NM_021005.4(NR2F2):c.856dup (p.Val286fs)	NR2F2	Pathogenic	criteria provided, single submitter
3062062	NM_021005.4(NR2F2):c.576del (p.Thr193fs)	NR2F2	Pathogenic	criteria provided, single submitter
3376906	NM_021005.4(NR2F2):c.232G>T (p.Glu78Ter)	NR2F2	Pathogenic	criteria provided, single submitter
3777741	NM_021005.4(NR2F2):c.368T>A (p.Ile123Asn)	NR2F2	Pathogenic	criteria provided, single submitter
446122	NM_021005.4(NR2F2):c.247G>T (p.Gly83Ter)	NR2F2	Pathogenic	no assertion criteria provided
4722378	NM_021005.4(NR2F2):c.139_155dup (p.Thr55fs)	NR2F2	Pathogenic	criteria provided, single submitter
848589	NM_021005.4(NR2F2):c.217C>T (p.Gln73Ter)	NR2F2	Pathogenic	criteria provided, single submitter
916034	NM_021005.4(NR2F2):c.97_103del (p.Pro33fs)	NR2F2	Pathogenic	criteria provided, single submitter
1805610	NM_021005.4(NR2F2):c.558dup (p.Arg187fs)	NR2F2	Likely pathogenic	criteria provided, single submitter
2429770	NM_021005.4(NR2F2):c.1019del (p.Lys340fs)	NR2F2	Likely pathogenic	criteria provided, single submitter
3062322	NM_021005.4(NR2F2):c.684del (p.Asn229fs)	NR2F2	Likely pathogenic	criteria provided, single submitter
3897577	NM_021005.4(NR2F2):c.305T>G (p.Phe102Cys)	NR2F2	Likely pathogenic	criteria provided, single submitter
547880	NM_021005.4(NR2F2):c.83_84dup (p.Val29fs)	NR2F2	Likely pathogenic	criteria provided, single submitter
548125	GRCh37/hg19 15q26.2(chr15:96878571-96880063)x1	NR2F2	Likely pathogenic	criteria provided, single submitter
2082452	NM_021005.4(NR2F2):c.1234G>T (p.Ala412Ser)	NR2F2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
598763	NM_021005.4(NR2F2):c.746G>A (p.Trp249Ter)	NR2F2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1012381	NM_021005.4(NR2F2):c.1081G>C (p.Gly361Arg)	NR2F2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1014312	NM_021005.4(NR2F2):c.309C>G (p.Phe103Leu)	NR2F2	Uncertain significance	criteria provided, single submitter
1016890	NM_021005.4(NR2F2):c.19A>G (p.Thr7Ala)	NR2F2	Uncertain significance	criteria provided, single submitter
1038040	NM_021005.4(NR2F2):c.682C>T (p.Arg228Trp)	NR2F2	Uncertain significance	criteria provided, single submitter
1064859	NM_021005.4(NR2F2):c.269A>G (p.His90Arg)	NR2F2	Uncertain significance	criteria provided, multiple submitters, no conflicts
128234	NM_021005.4(NR2F2):c.210GCA[6] (p.Gln75dup)	NR2F2	Uncertain significance	criteria provided, single submitter
1321294	NM_021005.4(NR2F2):c.691C>A (p.Pro231Thr)	NR2F2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NR2F2	Definitive	Autosomal dominant	NR2F2 related multiple congenital anomalies/dysmorphic syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NR2F2	Orphanet:99067	Complete atrioventricular septal defect with ventricular hypoplasia
NR2F2	Orphanet:99068	Complete atrioventricular septal defect-tetralogy of Fallot
CRELD1	Orphanet:576235	Partial atrioventricular septal defect without ventricular hypoplasia
CRELD1	Orphanet:99067	Complete atrioventricular septal defect with ventricular hypoplasia
CRELD1	Orphanet:99068	Complete atrioventricular septal defect-tetralogy of Fallot

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
NR2F2	HGNC:7976	ENSG00000185551	P24468	COUP transcription factor 2	gencc,clinvar
BMP7	HGNC:1074	ENSG00000101144	P18075	Bone morphogenetic protein 7	clinvar
XIRP2	HGNC:14303	ENSG00000163092	A4UGR9	Xin actin-binding repeat-containing protein 2	clinvar
CRELD1	HGNC:14630	ENSG00000163703	Q96HD1	Protein disulfide isomerase CRELD1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NR2F2	COUP transcription factor 2	Ligand-activated transcription factor.
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.
XIRP2	Xin actin-binding repeat-containing protein 2	Protects actin filaments from depolymerization.
CRELD1	Protein disulfide isomerase CRELD1	Protein disulfide isomerase.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · 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
Nuclear receptor	1	96.5×	0.021
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NR2F2	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
BMP7	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
XIRP2	Other/Unknown	no		Actin-binding_Xin_repeat, XIRP1/XIRP2
CRELD1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardia of stomach	1
dorsal root ganglion	1
urethra	1
endometrium epithelium	1
pigmented layer of retina	1
ventricular zone	1
biceps brachii	1
deltoid	1
quadriceps femoris	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NR2F2	289	ubiquitous	marker	urethra, cardia of stomach, dorsal root ganglion
BMP7	243	broad	marker	pigmented layer of retina, ventricular zone, endometrium epithelium
XIRP2	150	tissue_specific	marker	deltoid, biceps brachii, quadriceps femoris
CRELD1	134	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BMP7	3,134
NR2F2	2,741
XIRP2	1,735
CRELD1	1,018

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BMP7	P18075	4
NR2F2	P24468	1
XIRP2	A4UGR9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CRELD1	Q96HD1	81.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 4 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
Transcriptional regulation of brown and beige adipocyte differentiation	1	380.7×	0.027	BMP7
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	1	126.9×	0.027	BMP7
Elastic fibre formation	1	112.0×	0.027	BMP7
Molecules associated with elastic fibres	1	102.9×	0.027	BMP7
Sensory processing of sound by outer hair cells of the cochlea	1	68.0×	0.029	XIRP2
Sensory processing of sound by inner hair cells of the cochlea	1	54.4×	0.029	XIRP2
Adipogenesis	1	52.1×	0.029	BMP7
Transcriptional regulation of white adipocyte differentiation	1	43.3×	0.029	NR2F2
Interaction of NuRD complexes with transcription factors	1	42.3×	0.029	NR2F2
Extracellular matrix organization	1	21.0×	0.051	BMP7
Developmental Biology	1	4.8×	0.194	BMP7

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
radial pattern formation	1	4213.0×	0.005	NR2F2
negative regulation of mesenchymal cell apoptotic process involved in nephron morphogenesis	1	4213.0×	0.005	BMP7
mesenchymal cell apoptotic process involved in nephron morphogenesis	1	4213.0×	0.005	BMP7
negative regulation of glomerular mesangial cell proliferation	1	2106.5×	0.005	BMP7
nephrogenic mesenchyme morphogenesis	1	2106.5×	0.005	BMP7
negative regulation of striated muscle cell apoptotic process	1	1404.3×	0.005	BMP7
neural fold elevation formation	1	1404.3×	0.005	BMP7
lymphatic endothelial cell fate commitment	1	1404.3×	0.005	NR2F2
monocyte aggregation	1	1404.3×	0.005	BMP7
metanephric mesenchyme morphogenesis	1	1404.3×	0.005	BMP7
metanephric mesenchymal cell proliferation involved in metanephros development	1	1404.3×	0.005	BMP7
positive regulation of hyaluranon cable assembly	1	1404.3×	0.005	BMP7
positive regulation of cardiac neural crest cell migration involved in outflow tract morphogenesis	1	1404.3×	0.005	BMP7
response to estradiol	2	99.1×	0.005	NR2F2, BMP7
negative regulation of prostatic bud formation	1	1053.2×	0.006	BMP7
allantois development	1	1053.2×	0.006	BMP7
regulation of branching involved in prostate gland morphogenesis	1	842.6×	0.007	BMP7
regulation of removal of superoxide radicals	1	702.2×	0.007	BMP7
negative regulation of mitotic nuclear division	1	601.9×	0.007	BMP7
mesenchyme development	1	601.9×	0.007	BMP7
regulation of actin filament organization	1	601.9×	0.007	XIRP2
pericardium morphogenesis	1	526.6×	0.007	BMP7
ameloblast differentiation	1	526.6×	0.007	BMP7
mesenchymal cell differentiation	1	526.6×	0.007	BMP7
chorio-allantoic fusion	1	526.6×	0.007	BMP7
positive regulation of epithelial cell differentiation	1	468.1×	0.007	BMP7
heart trabecula morphogenesis	1	468.1×	0.007	BMP7
cardiac septum development	1	421.3×	0.007	CRELD1
mesonephros development	1	383.0×	0.007	BMP7
maternal placenta development	1	383.0×	0.007	NR2F2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NR2F2	3	3
BMP7	0	0
XIRP2	0	0
CRELD1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CARBOXYAMIDOTRIAZOLE	3	NR2F2
CYCLOHEXIMIDE	2	NR2F2
CHLORMIDAZOLE	2	NR2F2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NR2F2	2	Binding:1, Functional:1

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

3 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)
CARBOXYAMIDOTRIAZOLE	3	NR2F2
CYCLOHEXIMIDE	2	NR2F2
CHLORMIDAZOLE	2	NR2F2

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	1	NR2F2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	BMP7, XIRP2, CRELD1

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)
BMP7	0	—
XIRP2	0	—
CRELD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.