Atrial septal defect, ostium secundum type

Summary

Atrial septal defect, ostium secundum type (MONDO:0020434) is a disease with 5 cohort genes and 1 clinical trial.

At a glance

• Cohort genes: 5
• ClinVar variants: 7
• Phenotypes (HPO): 35
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0012382	Left-to-right shunt	Very frequent (80-99%)
HP:0001962	Palpitations	Frequent (30-79%)
HP:0002875	Exertional dyspnea	Frequent (30-79%)
HP:0003546	Exercise intolerance	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0030718	Right atrial enlargement	Frequent (30-79%)
HP:0031664	Systolic heart murmur	Frequent (30-79%)
HP:0001633	Abnormal mitral valve morphology	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0001653	Mitral regurgitation	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0004749	Atrial flutter	Occasional (5-29%)
HP:0004755	Supraventricular tachycardia	Occasional (5-29%)
HP:0005110	Atrial fibrillation	Occasional (5-29%)
HP:0005115	Supraventricular arrhythmia	Occasional (5-29%)
HP:0005133	Right ventricular dilatation	Occasional (5-29%)
HP:0005162	Abnormal left ventricular function	Occasional (5-29%)
HP:0005180	Tricuspid regurgitation	Occasional (5-29%)
HP:0005957	Breathing dysregulation	Occasional (5-29%)
HP:0010741	Pedal edema	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0011705	First degree atrioventricular block	Occasional (5-29%)
HP:0011710	Bundle branch block	Occasional (5-29%)
HP:0012250	ST segment depression	Occasional (5-29%)
HP:0012764	Orthopnea	Occasional (5-29%)
HP:0000961	Cyanosis	Very rare (<1-4%)
HP:0001279	Syncope	Very rare (<1-4%)
HP:0001297	Stroke	Very rare (<1-4%)
HP:0001708	Right ventricular failure	Very rare (<1-4%)
HP:0002090	Pneumonia	Very rare (<1-4%)
HP:0002326	Transient ischemic attack	Very rare (<1-4%)
HP:0002718	Recurrent bacterial infections	Very rare (<1-4%)
HP:0005317	Increased pulmonary vascular resistance	Very rare (<1-4%)
HP:0006536	Airway obstruction	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	atrial septal defect, ostium secundum type
Mondo ID	MONDO:0020434
Orphanet	99103
ICD-11	1875768490
UMLS	C0344724
MedGen	91034
GARD	0005865
MedDRA	10031302, 10031303
Is cancer (heuristic)	no

Also known as: ASD ostium secundum type · ASD, ostium secundum type · osASD · ostium secundum ASD · ostium secundum atrial septal defect

Data availability: 7 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › congenital heart disease › heart septal defect › atrial septal defect › atrial septal defect, ostium secundum type

Related subtypes (14): Lutembacher syndrome, atrial septal defect 1, atrial septal defect 7, atrial septal defect 2, atrial septal defect 4, atrial septal defect 5, atrial septal defect 6, atrial septal defect 3, atrial septal defect 8, atrial septal defect 9, atrial septal defect, coronary sinus type, atrial septal defect, sinus venosus type, atrial septal defect, ostium primum type, patent foramen ovale

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 pathogenic, 2 uncertain significance, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
373443	NM_001292034.3(TAB2):c.1039C>T (p.Arg347Ter)	LOC126859827	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804031	NM_002804.5(PSMC3):c.910C>T (p.Arg304Trp)	PSMC3	Pathogenic	criteria provided, single submitter
13329	NM_002834.5(PTPN11):c.184T>G (p.Tyr62Asp)	PTPN11	Pathogenic	reviewed by expert panel
495227	NM_181486.4(TBX5):c.1221C>G (p.Tyr407Ter)	TBX5	Pathogenic	criteria provided, single submitter
267834	46;X;t(Y;16)(q11.23;p11.2);t(6;21)(p21.3;p13)dn		Likely pathogenic	criteria provided, single submitter
268042	46;XY;t(18;20)(q21.1;p11.23)dn		Uncertain significance	criteria provided, single submitter
523385	NM_001009944.3(PKD1):c.226C>T (p.His76Tyr)	PKD1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBX5	Orphanet:101016	Romano-Ward syndrome
TBX5	Orphanet:392	Holt-Oram syndrome
PKD1	Orphanet:730	Autosomal dominant polycystic kidney disease
PKD1	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
PRKD1	Orphanet:276145	Malignant epithelial tumor of salivary glands
PRKD1	Orphanet:708019	Congenital heart defect-ectodermal dysplasia- brachydactyly-telangiectasia syndrome
PTPN11	Orphanet:2499	Metachondromatosis
PTPN11	Orphanet:500	Noonan syndrome with multiple lentigines
PTPN11	Orphanet:648	Noonan syndrome
PTPN11	Orphanet:86834	Juvenile myelomonocytic leukemia

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBX5	HGNC:11604	ENSG00000089225	Q99593	T-box transcription factor TBX5	clinvar
PKD1	HGNC:9008	ENSG00000008710	P98161	Polycystin-1	clinvar
PRKD1	HGNC:9407	ENSG00000184304	Q15139	Serine/threonine-protein kinase D1	clinvar
PSMC3	HGNC:9549	ENSG00000165916	P17980	26S proteasome regulatory subunit 6A	clinvar
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBX5	T-box transcription factor TBX5	DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation.
PKD1	Polycystin-1	Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B.
PRKD1	Serine/threonine-protein kinase D1	Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and tr…
PSMC3	26S proteasome regulatory subunit 6A	Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.6

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
Phosphatase	1	16.8×	0.280
Antibody/Immunoglobulin	1	5.8×	0.280
Kinase	1	5.5×	0.280
Transcription factor	1	1.6×	0.595
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBX5	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
PKD1	Antibody/Immunoglobulin	yes		GPS, LRRNT, PC1
PRKD1	Kinase	yes	2.7.11.13	Prot_kinase_dom, PH_domain, PKC_DAG/PE
PSMC3	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
cardiac muscle of right atrium	1
tendon of biceps brachii	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
seminal vesicle	1
thoracic aorta	1
ventricular zone	1
apex of heart	1
gastrocnemius	1
muscle of leg	1
dorsal motor nucleus of vagus nerve	1
globus pallidus	1
medial globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBX5	129	broad	marker	tendon of biceps brachii, cardiac muscle of right atrium, buccal mucosa cell
PKD1	290		marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PRKD1	239	ubiquitous	marker	ventricular zone, seminal vesicle, thoracic aorta
PSMC3	289	ubiquitous	marker	apex of heart, gastrocnemius, muscle of leg
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTPN11	6,009
PSMC3	4,843
TBX5	2,250
PRKD1	2,131
PKD1	1,370

Intra-cohort edges

A	B	Sources
PKD1	PRKD1	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSMC3	P17980	130
PTPN11	Q06124	115
PKD1	P98161	13
TBX5	Q99593	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRKD1	Q15139	68.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 134. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MET activates PTPN11	1	456.8×	0.039	PTPN11
Co-inhibition by BTLA	1	456.8×	0.039	PTPN11
STAT5 Activation	1	326.3×	0.039	PTPN11
Netrin mediated repulsion signals	1	253.8×	0.039	PTPN11
MAPK1 (ERK2) activation	1	228.4×	0.039	PTPN11
STAT5 activation downstream of FLT3 ITD mutants	1	228.4×	0.039	PTPN11
MAPK3 (ERK1) activation	1	207.6×	0.039	PTPN11
Signaling by Leptin	1	207.6×	0.039	PTPN11
Interleukin-6 signaling	1	190.3×	0.039	PTPN11
Activated NTRK2 signals through FRS2 and FRS3	1	190.3×	0.039	PTPN11
PECAM1 interactions	1	175.7×	0.039	PTPN11
Regulation of IFNG signaling	1	163.1×	0.039	PTPN11
Prolactin receptor signaling	1	152.3×	0.039	PTPN11
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	152.3×	0.039	TBX5
Signaling by FLT3 ITD and TKD mutants	1	152.3×	0.039	PTPN11
Spry regulation of FGF signaling	1	142.8×	0.039	PTPN11
Signal regulatory protein family interactions	1	134.3×	0.039	PTPN11
Platelet sensitization by LDL	1	134.3×	0.039	PTPN11
Physiological factors	1	134.3×	0.039	TBX5
Regulation of RUNX1 Expression and Activity	1	134.3×	0.039	PTPN11
GAB1 signalosome	1	126.9×	0.039	PTPN11
PI-3K cascade:FGFR3	1	126.9×	0.039	PTPN11
Tie2 Signaling	1	120.2×	0.039	PTPN11
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1	120.2×	0.039	PTPN11
PI-3K cascade:FGFR4	1	114.2×	0.039	PTPN11
Signaling by CSF3 (G-CSF)	1	114.2×	0.039	PTPN11
FRS-mediated FGFR3 signaling	1	108.8×	0.039	PTPN11
Co-inhibition by CTLA4	1	103.8×	0.039	PTPN11
Co-inhibition by PD-1	1	103.8×	0.039	PTPN11
VxPx cargo-targeting to cilium	1	103.8×	0.039	PKD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
genitalia development	2	674.1×	6e-04	PKD1, PTPN11
heart development	3	47.2×	0.002	TBX5, PKD1, PTPN11
host-mediated perturbation of viral transcription	1	3370.4×	0.006	PSMC3
negative regulation of cortisol secretion	1	3370.4×	0.006	PTPN11
negative regulation of growth hormone secretion	1	3370.4×	0.006	PTPN11
cell migration involved in coronary vasculogenesis	1	3370.4×	0.006	TBX5
metanephric distal tubule morphogenesis	1	3370.4×	0.006	PKD1
positive regulation of cardiac conduction	1	3370.4×	0.006	TBX5
cardiac left ventricle formation	1	1685.2×	0.006	TBX5
regulation of skeletal muscle contraction by modulation of calcium ion sensitivity of myofibril	1	1685.2×	0.006	PRKD1
microvillus organization	1	1685.2×	0.006	PTPN11
atrioventricular node cell fate commitment	1	1685.2×	0.006	TBX5
intestinal epithelial cell migration	1	1685.2×	0.006	PTPN11
nitrogen cycle metabolic process	1	1685.2×	0.006	PKD1
mesonephric tubule development	1	1685.2×	0.006	PKD1
bundle of His cell to Purkinje myocyte communication by electrical coupling	1	1685.2×	0.006	TBX5
positive regulation of cell communication by electrical coupling involved in cardiac conduction	1	1685.2×	0.006	TBX5
integrin-mediated signaling pathway	2	64.2×	0.006	PRKD1, PTPN11
positive regulation of transcription by RNA polymerase II	4	11.9×	0.006	TBX5, PKD1, PRKD1, PSMC3
atrioventricular bundle cell differentiation	1	1123.5×	0.007	TBX5
cerebellar cortex formation	1	1123.5×	0.007	PTPN11
lymph vessel morphogenesis	1	1123.5×	0.007	PKD1
metanephric proximal tubule development	1	1123.5×	0.007	PKD1
positive regulation of secondary heart field cardioblast proliferation	1	1123.5×	0.007	TBX5
bundle of His development	1	842.6×	0.007	TBX5
calcium-independent cell-matrix adhesion	1	842.6×	0.007	PKD1
positive regulation of cardioblast differentiation	1	842.6×	0.007	TBX5
regulation of type I interferon-mediated signaling pathway	1	842.6×	0.007	PTPN11
atrioventricular node cell development	1	842.6×	0.007	TBX5
cellular response to norepinephrine stimulus	1	842.6×	0.007	PRKD1

Therapeutics

Drug target analysis

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

Druggability breadth: 5 of 5 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PRKD1	INGENOL MEBUTATE
PSMC3	BORTEZOMIB
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKD1	26	4
PTPN11	8	4
PSMC3	2	4
TBX5	0	0
PKD1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
BORTEZOMIB	4	PSMC3
CARFILZOMIB	4	PSMC3
ESTRAMUSTINE PHOSPHATE	4	PTPN11
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
ENOXOLONE	2	PTPN11
CEFSULODIN	2	PTPN11
BATOPROTAFIB	2	PTPN11
VOCIPROTAFIB	2	PTPN11
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PRKD1	660	Binding:650, Functional:10
PTPN11	588	Binding:585, Functional:2, ADMET:1
PKD1	27	Binding:27
PSMC3	27	Binding:27
TBX5	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRKD1	2.7.11.13	protein kinase C
PTPN11	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PRKD1	660
PTPN11	588

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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)
INGENOL MEBUTATE	4	PRKD1
MIDOSTAURIN	4	PRKD1
TAMOXIFEN	4	PRKD1
NERATINIB	4	PRKD1
BRIGATINIB	4	PRKD1
NINTEDANIB	4	PRKD1
SUNITINIB	4	PRKD1
CRIZOTINIB	4	PRKD1
GEFITINIB	4	PRKD1
BORTEZOMIB	4	PSMC3
CARFILZOMIB	4	PSMC3
ESTRAMUSTINE PHOSPHATE	4	PTPN11
SURAMIN	3	PRKD1
FASUDIL	3	PRKD1
ALVOCIDIB	3	PRKD1
LESTAURTINIB	3	PRKD1
PHORBOL MYRISTATE ACETATE	2	PRKD1
EDELFOSINE	2	PRKD1
UPROSERTIB	2	PRKD1
UCN-01	2	PRKD1
SU-014813	2	PRKD1
AT-9283	2	PRKD1
BI-2536	2	PRKD1
ENOXOLONE	2	PTPN11
CEFSULODIN	2	PTPN11
BATOPROTAFIB	2	PTPN11
VOCIPROTAFIB	2	PTPN11
KW-2449	1	PRKD1
BMS-387032	1	PRKD1
PF-03758309	1	PRKD1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	PRKD1, PSMC3, PTPN11
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PKD1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TBX5

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)
PKD1	27	PRKD1
TBX5	1	—

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
NCT02601768	Not specified	UNKNOWN	Occluder Size Determination in Transcatheter ASD II Closure Based on 3D TEE Assessment