Congenital heart malformation

Summary

Congenital heart malformation (MONDO:0019512) is a disease (an umbrella term covering 26 Mondo subtypes) with 4 cohort genes (3 GWAS associations across 5 studies) and 3 clinical trials.

At a glance

• Prevalence: >1 / 1000 (Canada) [Orphanet-validated]
• Umbrella term: 26 Mondo subtypes
• Cohort genes: 4
• GWAS associations: 3
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	>1 / 1000	223	Canada	Validated
Prevalence at birth	1-9 / 100 000	7.8	Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital heart malformation
Mondo ID	MONDO:0019512
EFO	EFO:0005269
Orphanet	88991
UMLS	C3649636
MedGen	1680993
Is cancer (heuristic)	no

Also known as: congenital heart malformation · disorder of heart development · heart development disease

Data availability: 3 GWAS associations (5 studies) · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 26 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › congenital anomaly of cardiovascular system › congenital heart malformation

Related subtypes (4): venous hemangioma, congenital heart disease, congenital arteriovenous fistula, persistent fetal circulation syndrome

Subtypes (26): transposition of the great arteries, congenital left-sided heart lesions, interventricular septum aneurysm, congenital heart defects, multiple types, 2, coronary artery congenital malformation, criss-cross heart, triatrial heart, familial idiopathic dilatation of the right atrium, cardiac diverticulum, conotruncal heart malformations, congenital mitral malformation, congenital pericardium anomaly, ectopia cordis, visceral heterotaxy, mesocardia, univentricular cardiopathy, congenital anomaly of the great arteries, Laubry-Pezzi syndrome, congenital Gerbode defect, juxtaposition of the atrial appendages, ectasia of the right atrial appendage, ectasia of the left appendage, atrial septal aneurysm, congenital acardia, congenital right-sided heart lesions, congenital heart defects, multiple types, 1, X-linked

Genetics & variants

GWAS landscape

3 GWAS associations across 5 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1531070	5e-12	MAML3	A	1.4
rs2474937	8e-10	RNA5SP56 - PSMC1P12	C	1.4
rs137903200	2e-07	LINC02854 - LINC01445	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST013022	Trevino CE	2020	3,000	8,135	Identifying genetic factors that contribute to the increased risk of congenital heart defects in infants with Down syndrome.
GCST90651938	Liu TY	2025	1,472	234,318	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90474260	UK Biobank Whole-Genome Sequencing Consortium	2025	1,275	457,165	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST002036	Hu Z	2013	945	1,246	A genome-wide association study identifies two risk loci for congenital heart malformations in Han Chinese populations.
GCST90474262	UK Biobank Whole-Genome Sequencing Consortium	2025	435	458,005	Whole-genome sequencing of 490,640 UK Biobank participants.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	3

MAF distribution

Bucket	Variants
common (>=0.05)	2
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intergenic_variant	2
intron_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1531070	4	139874173	G>A	0.11	intron_variant	MAML3	5e-12	Tier 4: intronic/intergenic
rs2474937	1	118360355	A>C,G,T	0.08	intergenic_variant	RNA5SP56 - PSMC1P12	8e-10	Tier 4: intronic/intergenic
rs137903200	7	54076642	C>CA		intergenic_variant	LINC02854 - LINC01445	2e-07	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 9 · 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
FOXH1	Moderate	Autosomal dominant	congenital heart disease	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXH1	Orphanet:220386	Semilobar holoprosencephaly
FOXH1	Orphanet:280195	Septopreoptic holoprosencephaly
FOXH1	Orphanet:280200	Microform holoprosencephaly
FOXH1	Orphanet:93924	Lobar holoprosencephaly
FOXH1	Orphanet:93925	Alobar holoprosencephaly
FOXH1	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
TBX15	Orphanet:93333	Pelviscapular dysplasia
SPAG17	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
SPAG17	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	3
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FOXH1	HGNC:3814	ENSG00000160973	O75593	Forkhead box protein H1	gencc
TBX15	HGNC:11594	ENSG00000092607	Q96SF7	T-box transcription factor TBX15	gwas
MAML3	HGNC:16272	ENSG00000196782	Q96JK9	Mastermind-like protein 3	gwas
SPAG17	HGNC:26620	ENSG00000155761	Q6Q759	Sperm-associated antigen 17	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXH1	Forkhead box protein H1	Transcriptional activator.
TBX15	T-box transcription factor TBX15	Probable transcriptional regulator involved in the development of the skeleton of the limb, vertebral column and head.
MAML3	Mastermind-like protein 3	Acts as a transcriptional coactivator for NOTCH proteins.
SPAG17	Sperm-associated antigen 17	Component of the central pair apparatus of ciliary axonemes.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 2 · 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
Transcription factor	2	4.1×	0.149
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOXH1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_2, WH-like_DNA-bd_sf
TBX15	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
MAML3	Other/Unknown	no		Mastermind-like_N, MAML1-3, MAML_N_sf
SPAG17	Other/Unknown	no		SPAG17

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
diaphragm	1
male germ line stem cell (sensu Vertebrata) in testis	1
olfactory bulb	1
gastrocnemius	1
muscle of leg	1
skeletal muscle tissue of rectus abdominis	1
corpus epididymis	1
esophagus squamous epithelium	1
germinal epithelium of ovary	1
bronchial epithelial cell	1
right uterine tube	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXH1	124	broad	marker	diaphragm, male germ line stem cell (sensu Vertebrata) in testis, olfactory bulb
TBX15	172	broad	marker	gastrocnemius, muscle of leg, skeletal muscle tissue of rectus abdominis
MAML3	235	ubiquitous	marker	germinal epithelium of ovary, esophagus squamous epithelium, corpus epididymis
SPAG17	173	broad	marker	right uterine tube, bronchial epithelial cell, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPAG17	1,801
FOXH1	1,618
MAML3	1,215
TBX15	1,204

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FOXH1	O75593	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SPAG17	Q6Q759	64.20
TBX15	Q96SF7	61.41
MAML3	Q96JK9	47.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 4 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
NOTCH2 intracellular domain regulates transcription	1	475.8×	0.010	MAML3
RUNX3 regulates NOTCH signaling	1	407.9×	0.010	MAML3
Formation of axial mesoderm	1	407.9×	0.010	FOXH1
Signaling by Activin	1	380.7×	0.010	FOXH1
Regulation of beta-cell development	1	356.9×	0.010	MAML3
Signaling by NOTCH2	1	356.9×	0.010	MAML3
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	356.9×	0.010	MAML3
Germ layer formation at gastrulation	1	335.9×	0.010	FOXH1
NOTCH4 Intracellular Domain Regulates Transcription	1	285.5×	0.010	MAML3
Signaling by NOTCH3	1	259.6×	0.010	MAML3
Signaling by NODAL	1	248.3×	0.010	FOXH1
Signaling by NOTCH4	1	248.3×	0.010	MAML3
NOTCH3 Intracellular Domain Regulates Transcription	1	219.6×	0.010	MAML3
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	203.9×	0.010	MAML3
Signaling by NOTCH1 in Cancer	1	203.9×	0.010	MAML3
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	203.9×	0.010	MAML3
Notch-HLH transcription pathway	1	203.9×	0.010	MAML3
Formation of paraxial mesoderm	1	203.9×	0.010	MAML3
Pre-NOTCH Expression and Processing	1	184.2×	0.010	MAML3
Signaling by NOTCH1	1	178.4×	0.010	MAML3
Transcriptional regulation by RUNX3	1	135.9×	0.012	MAML3
Gastrulation	1	129.8×	0.012	MAML3
NOTCH1 Intracellular Domain Regulates Transcription	1	119.0×	0.013	MAML3
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	98.5×	0.014	MAML3
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	98.5×	0.014	MAML3
Signaling by NOTCH	1	87.8×	0.015	MAML3
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	73.2×	0.018	MAML3
Pre-NOTCH Transcription and Translation	1	61.4×	0.020	MAML3
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.042	MAML3
RNA Polymerase II Transcription	1	11.3×	0.101	MAML3

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
intramanchette transport	1	2106.5×	0.009	SPAG17
embryonic heart tube anterior/posterior pattern specification	1	1404.3×	0.009	FOXH1
axial mesoderm development	1	842.6×	0.009	FOXH1
axonemal central apparatus assembly	1	702.2×	0.009	SPAG17
positive regulation of transcription of Notch receptor target	1	601.9×	0.009	MAML3
determination of left/right asymmetry in lateral mesoderm	1	468.1×	0.009	FOXH1
secondary heart field specification	1	383.0×	0.009	FOXH1
cardiac right ventricle morphogenesis	1	351.1×	0.009	FOXH1
manchette assembly	1	324.1×	0.009	SPAG17
hepatocyte differentiation	1	300.9×	0.009	FOXH1
nodal signaling pathway	1	280.9×	0.009	FOXH1
ventricular trabecula myocardium morphogenesis	1	263.3×	0.009	FOXH1
negative regulation of androgen receptor signaling pathway	1	234.1×	0.009	FOXH1
aorta morphogenesis	1	221.7×	0.009	FOXH1
epithelial cilium movement involved in extracellular fluid movement	1	191.5×	0.010	SPAG17
motile cilium assembly	1	145.3×	0.011	SPAG17
embryonic cranial skeleton morphogenesis	1	145.3×	0.011	TBX15
cellular response to cytokine stimulus	1	135.9×	0.011	FOXH1
cell fate specification	1	131.7×	0.011	TBX15
positive regulation of DNA-templated transcription	2	14.0×	0.011	TBX15, FOXH1
outflow tract morphogenesis	1	76.6×	0.017	FOXH1
heart looping	1	66.9×	0.019	FOXH1
transforming growth factor beta receptor signaling pathway	1	39.8×	0.029	FOXH1
positive regulation of transcription by RNA polymerase II	2	7.4×	0.029	MAML3, FOXH1
Notch signaling pathway	1	35.4×	0.031	MAML3
spermatogenesis	1	8.8×	0.117	SPAG17
negative regulation of transcription by RNA polymerase II	1	4.4×	0.215	FOXH1
regulation of transcription by RNA polymerase II	1	2.9×	0.302	TBX15

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
FOXH1	0	0
TBX15	0	0
MAML3	0	0
SPAG17	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	4	FOXH1, TBX15, MAML3, SPAG17

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)
FOXH1	0	—
TBX15	0	—
MAML3	0	—
SPAG17	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2/PHASE3	1
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05101746	PHASE2/PHASE3	ENROLLING_BY_INVITATION	Nitric Oxide Effect on Brain and Kidney in Pediatric Patients Undergoing Cardiopulmonary Bypass
NCT07381530	PHASE2	SUSPENDED	Study of Cardioplegia in Cardiac Surgery Due to Congenital Heart Malformation in Children
NCT03047343	Not specified	COMPLETED	Evolution of Two Cohorts of Children (Univentricular and Bi-ventricular Heart) After Strapping of the Pulmonary Artery