Heart septal defect

Summary

Heart septal defect (MONDO:0002078) is a disease with 4 cohort genes (9 GWAS associations across 3 studies) and 3 clinical trials.

At a glance

• Cohort genes: 4
• GWAS associations: 9
• Clinical trials: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	heart septal defect
Mondo ID	MONDO:0002078
MeSH	D006343
DOID	DOID:1681
NCIT	C84482
SNOMED CT	253273004
UMLS	C0018816
MedGen	6752
Is cancer (heuristic)	no

Also known as: Cardiac septal defects · congenital septal defect · holes in the heart

Data availability: 9 GWAS associations (3 studies).

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › congenital heart disease › heart septal defect

Related subtypes (22): congenital heart defects, multiple types, tetralogy of fallot, heart defects-limb shortening syndrome, tricuspid atresia, patent ductus arteriosus, coronary artery congenital malformation, mitral atresia disorder, persistent truncus arteriosus, dextro-looped transposition of the great arteries, aortic valve atresia, congenital pulmonary veins anomaly, mehta lewis patton syndrome, structural congenital heart disease, multiple types - GATA4, GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetes, GATA5-related congenital heart defects, RBFOX2-related congenital heart disorder, syndromic congenital heart disease, ACTC1-related distal arthrogryposis with congenital heart disease, HAND1 related congenital heart defect, HAND2 related congenital heart defect, TFAP2B-related congenital heart disease spectrum disorder, PLD1-related congenital heart disease

Subtypes (3): ventricular septal defect, atrial septal defect, familial atrioventricular septal defect

Genetics & variants

GWAS landscape

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

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1293973611	1e-10	LINC03048	?	6.23
rs75230966	8e-09	WNT9B - GOSR2-DT	?	1.27
rs6824295	1e-08	STX18-AS1	?	1.23
rs187369228	2e-08	P3H2	?	2.97
rs72917381	2e-08	WDR7	?	5.93
rs185531658	6e-08	YTHDC2 - KCNN2	?	2.16
rs138741144	7e-08	ASIC2	?	2.46
rs150007890	1e-07	LINC00229 - ANP32BP2	?
rs870142	4e-07	STX18-AS1	?	1.4

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90570532	Broberg M	2024	1,955	392,428	Genome-wide association studies highlight novel risk loci for septal defects and left-sided congenital heart defects.
GCST011985	Lahm H	2020	1,074	8,486	Congenital heart disease risk loci identified by genome-wide association study in European patients.
GCST90651858	Liu TY	2025	765	234,318	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.

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	9

MAF distribution

Bucket	Variants
common (>=0.05)	4
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	5

Functional consequences

Consequence	Count
intron_variant	7
intergenic_variant	2

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1293973611	17	81382139	C>T		intron_variant	LINC03048	1e-10	Tier 4: intronic/intergenic
rs75230966	17	46890164	G>A	0.05	intergenic_variant	WNT9B - GOSR2-DT	8e-09	Tier 4: intronic/intergenic
rs6824295	4	4612553	C>G,T	0.05	intron_variant	STX18-AS1	1e-08	Tier 4: intronic/intergenic
rs187369228	3	190084650	A>G	0.05	intron_variant	P3H2	2e-08	Tier 4: intronic/intergenic
rs72917381	18	56878992	C>T		intron_variant	WDR7	2e-08	Tier 4: intronic/intergenic
rs185531658	5	113800824	T>C		intron_variant	YTHDC2 - KCNN2	6e-08	Tier 4: intronic/intergenic
rs138741144	17	33959545	G>A		intron_variant	ASIC2	7e-08	Tier 4: intronic/intergenic
rs150007890	22	44640790	G>A		intergenic_variant	LINC00229 - ANP32BP2	1e-07	Tier 4: intronic/intergenic
rs870142	4	4646320	C>G,T	0.05	intron_variant	STX18-AS1	4e-07	Tier 4: intronic/intergenic

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
P3H2	Orphanet:98619	Rare isolated myopia

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
WDR7	HGNC:13490	ENSG00000091157	Q9Y4E6	WD repeat-containing protein 7	gwas
P3H2	HGNC:19317	ENSG00000090530	Q8IVL5	Prolyl 3-hydroxylase 2	gwas
STX18-AS1	HGNC:48877	ENSG00000247708		STX18 antisense RNA 1	gwas
ASIC2	HGNC:99	ENSG00000108684	Q16515	Acid-sensing ion channel 2	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
P3H2	Prolyl 3-hydroxylase 2	Prolyl 3-hydroxylase that catalyzes the post-translational formation of 3-hydroxyproline on collagens.
ASIC2	Acid-sensing ion channel 2	Forms pH-gated trimeric sodium channels that act as postsynaptic excitatory sensors in the nervous system.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · 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
Scaffold/PPI	1	4.3×	0.441
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WDR7	Scaffold/PPI	no		WD40_rpt, Quinoprotein_ADH-like_sf, WD40/YVTN_repeat-like_dom_sf
P3H2	Enzyme (other)	yes	1.14.11.7	Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph, TPR-like_helical_dom_sf
STX18-AS1	Other/Unknown	no
ASIC2	Other/Unknown	no		ENaC, ENaC_chordates, ENaC_CS

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
adrenal tissue	1
cartilage tissue	1
metanephros cortex	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
sural nerve	1
anterior cingulate cortex	1
cingulate cortex	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WDR7	288	ubiquitous	yes	endothelial cell, middle temporal gyrus, Brodmann (1909) area 23
P3H2	215	ubiquitous	marker	adrenal tissue, cartilage tissue, metanephros cortex
STX18-AS1	162	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, sural nerve
ASIC2	131	tissue_specific	marker	prefrontal cortex, cingulate cortex, anterior cingulate cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WDR7	1,979
ASIC2	1,493
P3H2	895
STX18-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ASIC2	Q16515	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
P3H2	Q8IVL5	83.62
WDR7	Q9Y4E6	74.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Collagen biosynthesis and modifying enzymes	1	85.2×	0.028	P3H2
Stimuli-sensing channels	1	68.0×	0.028	ASIC2
Ion channel transport	1	48.0×	0.028	ASIC2
Transport of small molecules	1	12.6×	0.078	ASIC2

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
regulation of systemic arterial blood pressure by aortic arch baroreceptor feedback	1	2808.7×	0.004	ASIC2
peptidyl-proline hydroxylation	1	2808.7×	0.004	P3H2
detection of mechanical stimulus involved in sensory perception	1	936.2×	0.007	ASIC2
sensory perception of sour taste	1	561.7×	0.009	ASIC2
collagen metabolic process	1	351.1×	0.010	P3H2
regulation of vasoconstriction	1	267.5×	0.010	ASIC2
protein localization to synapse	1	255.3×	0.010	ASIC2
regulation of monoatomic ion transmembrane transport	1	244.2×	0.010	ASIC2
cellular response to acidic pH	1	244.2×	0.010	ASIC2
phototransduction	1	165.2×	0.013	ASIC2
regulation of postsynapse assembly	1	114.6×	0.017	ASIC2
positive regulation of synapse assembly	1	81.4×	0.017	ASIC2
cellular response to xenobiotic stimulus	1	80.2×	0.017	ASIC2
hematopoietic progenitor cell differentiation	1	79.1×	0.017	WDR7
synapse assembly	1	77.0×	0.017	ASIC2
regulation of membrane potential	1	77.0×	0.017	ASIC2
sodium ion transmembrane transport	1	67.7×	0.018	ASIC2
establishment of localization in cell	1	53.5×	0.022	ASIC2
sensory perception of sound	1	33.6×	0.033	ASIC2
negative regulation of cell population proliferation	1	14.0×	0.073	P3H2
negative regulation of apoptotic process	1	11.6×	0.084	ASIC2

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
WDR7	0	0
P3H2	0	0
STX18-AS1	0	0
ASIC2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
P3H2	1.14.11.7	procollagen-proline 3-dioxygenase

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

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	P3H2
E	Difficult family or no structure, no drug	3	WDR7, STX18-AS1, ASIC2

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)
WDR7	0	—
P3H2	0	—
STX18-AS1	0	—
ASIC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04591392	Not specified	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study of reSept ASD Occluder for Treating Secundum ASD
NCT07300358	Not specified	NOT_YET_RECRUITING	Study on the Safety and Effectiveness of a Biodegradable Patent Foramen Ovale Occluder System
NCT01385670	Not specified	UNKNOWN	InterSEPT: In-Tunnel SeptRx European PFO Trial