Atrial septal defect

Summary

Atrial septal defect (MONDO:0006664) is a disease (an umbrella term covering 15 Mondo subtypes) caused by MYH6 (GenCC Strong), with 17 cohort genes (4 GWAS associations across 6 studies) and 99 clinical trials. Top therapeutic interventions include thiamine ion, articaine, and fluorescein sodium.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide)
• Causal gene: MYH6 (GenCC Strong)
• Umbrella term: 15 Mondo subtypes
• Cohort genes: 17
• GWAS associations: 4
• ClinVar variants: 28
• Phenotypes (HPO): 19
• Clinical trials: 99

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	3	Worldwide	Not yet validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0001631	Atrial septal defect	Very frequent (80-99%)
HP:0001684	Secundum atrial septal defect	Very frequent (80-99%)
HP:0005110	Atrial fibrillation	Frequent (30-79%)
HP:0031664	Systolic heart murmur	Frequent (30-79%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0001640	Cardiomegaly	Occasional (5-29%)
HP:0001962	Palpitations	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002875	Exertional dyspnea	Occasional (5-29%)
HP:0004749	Atrial flutter	Occasional (5-29%)
HP:0005133	Right ventricular dilatation	Occasional (5-29%)
HP:0010445	Primum atrial septal defect	Occasional (5-29%)
HP:0011567	Sinus venosus atrial septal defect	Occasional (5-29%)
HP:0011712	Right bundle branch block	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0033567	Right axis deviation	Occasional (5-29%)
HP:0001297	Stroke	Very rare (<1-4%)
HP:0031297	Unroofed coronary sinus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	atrial septal defect
Mondo ID	MONDO:0006664
EFO	EFO:1000825
MeSH	D006344
OMIM	108800
Orphanet	1478
DOID	DOID:1882
ICD-10-CM	Q21.1
ICD-11	1285985084
NCIT	C84473
SNOMED CT	253366007
UMLS	C0018817
MedGen	6753
MedDRA	10003664, 10019308, 10068864
NORD	820
Is cancer (heuristic)	no

Also known as: ASD · atrial septal defect · Atrial Septal Defects · atrial septum defect · auricular septal defect · congenital atrial septal defect · interatrial septal defect · interauricular communication

Data availability: 28 ClinVar variants · 4 GWAS associations (6 studies) · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 15 Mondo subtypes.

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

Related subtypes (2): ventricular septal defect, familial atrioventricular septal defect

Subtypes (15): 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, ostium secundum type, 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

4 GWAS associations across 6 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
rs537462848	7e-16	PARP14 - HSPBAP1	C	3.2
rs146656031	1e-11	CUPIN1P - DYNAPP1	C	3.94
rs562239572	1e-11	NETO1-DT - LINC02864	A	3.69
rs371321364	2e-11	ROBO1	A	2.79

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90479068	Verma A	2024	1,217	448,902	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90436746	Zhou W	2018	586	406,165	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90080747	Backman JD	2021	554	387,345	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90084733	Backman JD	2021	554	387,345	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90480555	Verma A	2024	258	121,379	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90482446	Verma A	2024	258	121,379	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.

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	4

MAF distribution

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

Functional consequences

Consequence	Count
intergenic_variant	3
intron_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs537462848	3	122736164	C>A,T	0	intergenic_variant	PARP14 - HSPBAP1	7e-16	Tier 4: intronic/intergenic
rs146656031	18	54511706	C>T	0.001	intergenic_variant	CUPIN1P - DYNAPP1	1e-11	Tier 4: intronic/intergenic
rs562239572	18	73032133	A>G,T	0.001	intergenic_variant	NETO1-DT - LINC02864	1e-11	Tier 4: intronic/intergenic
rs371321364	3	79426971	A>C	0	intron_variant	ROBO1	2e-11	Tier 4: intronic/intergenic

ClinVar germline variants

28 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 7 likely pathogenic, 4 pathogenic, 2 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
267847	46;XY;t(9;11)(q34;p11.2)dn		Pathogenic	criteria provided, single submitter
267941	46;XY;inv(6)(p22q13)dn		Pathogenic	criteria provided, single submitter
523383	NM_000969.5(RPL5):c.74-1G>C	DIPK1A	Pathogenic	criteria provided, single submitter
523470	NM_004006.3(DMD):c.93+1G>C	DMD	Pathogenic	criteria provided, single submitter
519074	NM_004387.4(NKX2-5):c.491C>A (p.Ser164Ter)	NKX2-5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523473	NM_004387.4(NKX2-5):c.711C>A (p.Tyr237Ter)	NKX2-5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
267884	46;XY;t(3;5)(q23;q13)dn		Likely pathogenic	criteria provided, single submitter
268037	46;XY;t(2;14)(p22;q24.3)dn		Likely pathogenic	criteria provided, single submitter
523361	NM_000352.6(ABCC8):c.1793G>A (p.Arg598Gln)	ABCC8	Likely pathogenic	criteria provided, single submitter
523522	NM_017780.4(CHD7):c.2867C>A (p.Ser956Ter)	CHD7	Likely pathogenic	criteria provided, single submitter
523523	NM_018486.3(HDAC8):c.584T>G (p.Val195Gly)	HDAC8	Likely pathogenic	criteria provided, single submitter
523513	NM_015559.3(SETBP1):c.2614G>A (p.Gly872Arg)	SETBP1	Likely pathogenic	criteria provided, single submitter
626359	NM_181486.4(TBX5):c.253C>A (p.Pro85Thr)	TBX5	Likely pathogenic	no assertion criteria provided
549661	NM_004301.5(ACTL6A):c.1129C>T (p.Arg377Trp)	ACTL6A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
816865	NM_003072.5(SMARCA4):c.2900G>A (p.Arg967His)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
267820	46;XY;t(16;20)(q11.2;q13.2)dn		Uncertain significance	criteria provided, single submitter
267889	46;XX;inv(14)(q24.1q32.1)dn		Uncertain significance	criteria provided, single submitter
268042	46;XY;t(18;20)(q21.1;p11.23)dn		Uncertain significance	criteria provided, single submitter
35609	NM_000352.6(ABCC8):c.3517G>A (p.Val1173Met)	ABCC8	Uncertain significance	criteria provided, multiple submitters, no conflicts
2570675	NM_015089.4(CUL9):c.7237C>T (p.Arg2413Trp)	CUL9	Uncertain significance	criteria provided, single submitter
2570677	NM_015089.4(CUL9):c.2732C>T (p.Pro911Leu)	CUL9	Uncertain significance	criteria provided, single submitter
2571631	NM_014608.6(CYFIP1):c.1798T>C (p.Phe600Leu)	CYFIP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2571636	NM_014608.6(CYFIP1):c.1348G>T (p.Ala450Ser)	CYFIP1	Uncertain significance	criteria provided, single submitter
523539	NM_031407.7(HUWE1):c.6485G>C (p.Arg2162Pro)	HUWE1	Uncertain significance	criteria provided, single submitter
816905	NM_002430.3(MN1):c.3839del (p.Cys1280fs)	MN1	Uncertain significance	criteria provided, single submitter
403212	NM_053025.4(MYLK):c.3637G>A (p.Val1213Met)	MYLK	Uncertain significance	criteria provided, multiple submitters, no conflicts
180531	NM_005633.4(SOS1):c.1352C>A (p.Thr451Lys)	SOS1	Uncertain significance	no assertion criteria provided
36658	NM_004387.4(NKX2-5):c.543G>A (p.Gln181=)	NKX2-5	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 48 · 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
MYH6	Strong	Autosomal dominant	atrial septal defect	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYH6	Orphanet:154	Familial isolated dilated cardiomyopathy
MYH6	Orphanet:166282	Hereditary sick sinus syndrome
MYH6	Orphanet:99103	Atrial septal defect, ostium secundum type
SMARCA4	Orphanet:1465	Coffin-Siris syndrome
SMARCA4	Orphanet:231108	Rhabdoid tumor predisposition syndrome
SMARCA4	Orphanet:370396	Small cell carcinoma of the ovary
SMARCA4	Orphanet:466962	SMARCA4-deficient sarcoma of thorax
SOS1	Orphanet:2024	Hereditary gingival fibromatosis
SOS1	Orphanet:648	Noonan syndrome
TBX5	Orphanet:101016	Romano-Ward syndrome
TBX5	Orphanet:392	Holt-Oram syndrome
HDAC8	Orphanet:199	Cornelia de Lange syndrome
HDAC8	Orphanet:3459	Wilson-Turner syndrome
SETBP1	Orphanet:436151	Intellectual disability-expressive aphasia-facial dysmorphism syndrome
SETBP1	Orphanet:798	Schinzel-Giedion syndrome
CHD7	Orphanet:138	CHARGE syndrome
CHD7	Orphanet:39041	Omenn syndrome
CHD7	Orphanet:432	Normosmic congenital hypogonadotropic hypogonadism
CHD7	Orphanet:478	Kallmann syndrome
ACTL6A	Orphanet:528084	Non-specific syndromic intellectual disability
NKX2-5	Orphanet:101351	Familial isolated congenital asplenia
NKX2-5	Orphanet:1479	Atrial septal defect-atrioventricular conduction defects syndrome
NKX2-5	Orphanet:1627	Deletion 5q35 syndrome
NKX2-5	Orphanet:2248	Hypoplastic left heart syndrome
NKX2-5	Orphanet:3303	Tetralogy of Fallot
NKX2-5	Orphanet:334	Hereditary atrial fibrillation
NKX2-5	Orphanet:402075	Familial bicuspid aortic valve
NKX2-5	Orphanet:871	Hereditary progressive cardiac conduction defect
NKX2-5	Orphanet:95712	Thyroid ectopia
NKX2-5	Orphanet:95713	Athyreosis
NKX2-5	Orphanet:99103	Atrial septal defect, ostium secundum type
DMD	Orphanet:154	Familial isolated dilated cardiomyopathy
DMD	Orphanet:206546	Symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
DMD	Orphanet:777	X-linked non-syndromic intellectual disability
DMD	Orphanet:98895	Becker muscular dystrophy
DMD	Orphanet:98896	Duchenne muscular dystrophy
HUWE1	Orphanet:528084	Non-specific syndromic intellectual disability
ABCC8	Orphanet:276575	Autosomal dominant hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:276598	Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:552	MODY
ABCC8	Orphanet:79134	DEND syndrome
ABCC8	Orphanet:79643	Autosomal recessive hyperinsulinism due to SUR1 deficiency
ABCC8	Orphanet:99885	Isolated permanent neonatal diabetes mellitus
ABCC8	Orphanet:99886	Transient neonatal diabetes mellitus
MN1	Orphanet:263662	Familial multiple meningioma
MN1	Orphanet:693549	Facial dysmorphism-Intellectual disability-rhombencephalosynapsis syndrome
MYLK	Orphanet:2241	Megacystis-microcolon-intestinal hypoperistalsis syndrome
MYLK	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

Cohort genes → proteins

17 cohort genes, 17 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	17

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYH6	HGNC:7576	ENSG00000197616	P13533	Myosin-6	gencc
SMARCA4	HGNC:11100	ENSG00000127616	P51532	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	clinvar
SOS1	HGNC:11187	ENSG00000115904	Q07889	Son of sevenless homolog 1	clinvar
TBX5	HGNC:11604	ENSG00000089225	Q99593	T-box transcription factor TBX5	clinvar
HDAC8	HGNC:13315	ENSG00000147099	Q9BY41	Histone deacetylase 8	clinvar
CYFIP1	HGNC:13759	ENSG00000273749	Q7L576	Cytoplasmic FMR1-interacting protein 1	clinvar
SETBP1	HGNC:15573	ENSG00000152217	Q9Y6X0	SET-binding protein	clinvar
CUL9	HGNC:15982	ENSG00000112659	Q8IWT3	Cullin-9	clinvar
CHD7	HGNC:20626	ENSG00000171316	Q9P2D1	ATP-dependent chromatin remodeler CHD7	clinvar
ACTL6A	HGNC:24124	ENSG00000136518	O96019	Actin-like protein 6A	clinvar
NKX2-5	HGNC:2488	ENSG00000183072	P52952	Homeobox protein Nkx-2.5	clinvar
DMD	HGNC:2928	ENSG00000198947	P11532	Dystrophin	clinvar
HUWE1	HGNC:30892	ENSG00000086758	Q7Z6Z7	E3 ubiquitin-protein ligase HUWE1	clinvar
DIPK1A	HGNC:32213	ENSG00000154511	Q5T7M9	Divergent protein kinase domain 1A	clinvar
ABCC8	HGNC:59	ENSG00000006071	Q09428	ATP-binding cassette sub-family C member 8	clinvar
MN1	HGNC:7180	ENSG00000169184	Q10571	Transcriptional activator MN1	clinvar
MYLK	HGNC:7590	ENSG00000065534	Q15746	Myosin light chain kinase, smooth muscle	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYH6	Myosin-6	Muscle contraction.
SMARCA4	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SOS1	Son of sevenless homolog 1	Promotes the exchange of Ras-bound GDP by GTP.
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.
HDAC8	Histone deacetylase 8	Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4).
CYFIP1	Cytoplasmic FMR1-interacting protein 1	Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression.
CUL9	Cullin-9	Core component of a Cul9-RING ubiquitin-protein ligase complex composed of CUL9 and RBX1.
CHD7	ATP-dependent chromatin remodeler CHD7	ATP-dependent chromatin-remodeling factor, slides nucleosomes along DNA; nucleosome sliding requires ATP.
ACTL6A	Actin-like protein 6A	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
NKX2-5	Homeobox protein Nkx-2.5	Transcription factor required for the development of the heart and the spleen.
DMD	Dystrophin	Anchors the extracellular matrix to the cytoskeleton via F-actin.
HUWE1	E3 ubiquitin-protein ligase HUWE1	E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins.
ABCC8	ATP-binding cassette sub-family C member 8	Regulator subunit of pancreatic ATP-sensitive potassium channel (KATP), playing a major role in the regulation of insulin release.
MN1	Transcriptional activator MN1	Transcriptional activator which specifically regulates expression of TBX22 in the posterior region of the developing palate.
MYLK	Myosin light chain kinase, smooth muscle	Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC).

Protein-family classification

Druggable: 5 · Difficult: 6 · Unknown: 6 · Druggable fraction: 0.29

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
Transporter	1	4.6×	0.387
Kinase	2	3.3×	0.387
Scaffold/PPI	2	2.0×	0.387
Transcription factor	4	1.9×	0.387
Enzyme (other)	2	1.4×	0.505
Other/Unknown	6	0.6×	0.974

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYH6	Scaffold/PPI	no		Myosin_head_motor_dom-like, Myosin_tail, SH3_Myosin
SMARCA4	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
SOS1	Scaffold/PPI	no		DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain
TBX5	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
HDAC8	Enzyme (other)	yes	3.5.1.98	HDACs, HDAC_I/II, Ureohydrolase_dom_sf
CYFIP1	Other/Unknown	no		Cytoplasmic_FMR1-int, CYRIA/CYRIB_Rac1-bd
SETBP1	Other/Unknown	no		AT_hook_DNA-bd_motif
CUL9	Transcription factor	no		Znf_RING, IBR_dom, APC_su10/DOC_dom
CHD7	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
ACTL6A	Other/Unknown	no		Actin, Actin_CS, ATPase_NBD
NKX2-5	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
DMD	Transcription factor	no		Znf_ZZ, WW_dom, Actinin_actin-bd_CS
HUWE1	Enzyme (other)	yes	2.3.2.26	HECT_dom, WWE_dom, UBA-like_sf
DIPK1A	Kinase	yes		FAM69_kinase_dom, FAM69_N
ABCC8	Transporter	yes		ABCC8/9, ABCC8, ABC_transporter-like_ATP-bd
MN1	Other/Unknown	no		MN1
MYLK	Kinase	yes	2.7.11.18	Prot_kinase_dom, Ig_sub2, Ig_sub

Expression context

Cohort genes with no expression data: 0.

15 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)	17
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ganglionic eminence	3
cardiac atrium	2
cardiac muscle of right atrium	2
colonic epithelium	2
tendon of biceps brachii	2
buccal mucosa cell	2
vena cava	1
cervix squamous epithelium	1
cortical plate	1
jejunal mucosa	1
adrenal tissue	1
left adrenal gland	1
epithelium of esophagus	1
esophagus squamous epithelium	1
germinal epithelium of ovary	1
caput epididymis	1
ventricular zone	1
left testis	1
right frontal lobe	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYH6	154	tissue_specific	yes	cardiac muscle of right atrium, cardiac atrium, vena cava
SMARCA4	295	ubiquitous	marker	ganglionic eminence, cortical plate, cervix squamous epithelium
SOS1	289	ubiquitous	marker	colonic epithelium, jejunal mucosa, tendon of biceps brachii
TBX5	129	broad	marker	tendon of biceps brachii, cardiac muscle of right atrium, buccal mucosa cell
HDAC8	244	ubiquitous	marker	colonic epithelium, adrenal tissue, left adrenal gland
CYFIP1	295	ubiquitous	marker	esophagus squamous epithelium, germinal epithelium of ovary, epithelium of esophagus
SETBP1	280	ubiquitous	marker	ventricular zone, buccal mucosa cell, caput epididymis
CUL9	275	ubiquitous	marker	right testis, left testis, right frontal lobe
CHD7	269	ubiquitous	marker	secondary oocyte, cerebellar vermis, sural nerve
ACTL6A	272	ubiquitous	marker	primordial germ cell in gonad, calcaneal tendon, ganglionic eminence
NKX2-5	98	broad	yes	apex of heart, right atrium auricular region, cardiac atrium
DMD	295	ubiquitous	marker	trigeminal ganglion, skeletal muscle tissue of rectus abdominis, dorsal root ganglion
HUWE1	300	ubiquitous	marker	skin of leg, skin of abdomen, right lobe of thyroid gland
DIPK1A	275	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
ABCC8	185	broad	marker	islet of Langerhans, right hemisphere of cerebellum, cerebellar hemisphere
MN1	252	ubiquitous	marker	ganglionic eminence, vastus lateralis, skeletal muscle tissue of biceps brachii
MYLK	289	ubiquitous	marker	cauda epididymis, saphenous vein, seminal vesicle

Protein interactions among cohort

Intra-cohort edges: 8.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCA4	8,138
HUWE1	5,793
ACTL6A	5,583
CHD7	4,819
SOS1	3,625
MYH6	3,119
HDAC8	3,087
ABCC8	2,826
MYLK	2,763
DMD	2,479

Intra-cohort edges

A	B	Sources
ACTL6A	SMARCA4	biogrid_interaction, intact, string_interaction
CHD7	SMARCA4	intact
CUL9	CYFIP1	biogrid_interaction
MYH6	NKX2-5	string_interaction
MYH6	TBX5	string_interaction
NKX2-5	SMARCA4	string_interaction
NKX2-5	TBX5	biogrid_interaction, intact, string_interaction
SMARCA4	TBX5	string_interaction

Structural data

PDB: 13 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SOS1	Q07889	91
HDAC8	Q9BY41	53
SMARCA4	P51532	31
ACTL6A	O96019	25
HUWE1	Q7Z6Z7	19
ABCC8	Q09428	8
MYLK	Q15746	8
DMD	P11532	6
CYFIP1	Q7L576	5
TBX5	Q99593	4
CUL9	Q8IWT3	4
NKX2-5	P52952	4
CHD7	Q9P2D1	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DIPK1A	Q5T7M9	83.20
MYH6	P13533	74.91
SETBP1	Q9Y6X0	43.30
MN1	Q10571	42.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 207. Enrichment computed across 17 evidence-associated genes (14 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 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
YAP1- and WWTR1 (TAZ)-stimulated gene expression	2	108.8×	0.008	TBX5, NKX2-5
Physiological factors	2	96.0×	0.008	TBX5, NKX2-5
Formation of the non-canonical BAF (ncBAF) complex	2	96.0×	0.008	SMARCA4, ACTL6A
Formation of the canonical BAF (cBAF) complex	2	90.6×	0.008	SMARCA4, ACTL6A
Formation of the polybromo-BAF (pBAF) complex	2	90.6×	0.008	SMARCA4, ACTL6A
Formation of the embryonic stem cell BAF (esBAF) complex	2	85.9×	0.008	SMARCA4, ACTL6A
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	2	65.3×	0.012	SMARCA4, ACTL6A
Cardiogenesis	2	60.4×	0.012	TBX5, NKX2-5
Regulation of endogenous retroelements	2	52.6×	0.014	SMARCA4, ACTL6A
Muscle contraction	3	16.5×	0.014	TBX5, MYH6, MYLK
Striated Muscle Contraction	2	44.1×	0.017	DMD, MYH6
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	2	42.9×	0.017	SMARCA4, ACTL6A
Regulation of MITF-M-dependent genes involved in pigmentation	2	37.9×	0.019	SMARCA4, ACTL6A
Downstream signaling of activated FGFR2	1	407.9×	0.032	SOS1
Downstream signaling of activated FGFR3	1	407.9×	0.032	SOS1
Defective ABCC8 can cause hypo- and hyper-glycemias	1	407.9×	0.032	ABCC8
MITF-M-dependent gene expression	2	25.9×	0.032	SMARCA4, ACTL6A
Downstream signaling of activated FGFR4	1	271.9×	0.039	SOS1
RMTs methylate histone arginines	2	20.9×	0.039	SMARCA4, ACTL6A
Transcriptional regulation by RUNX1	2	20.9×	0.039	SMARCA4, ACTL6A
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	2	20.9×	0.039	SMARCA4, HDAC8
ATP sensitive Potassium channels	1	203.9×	0.046	ABCC8
Signaling by ERBB2 in Cancer	1	163.1×	0.051	SOS1
Signaling by EGFRvIII in Cancer	1	163.1×	0.051	SOS1
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	2	16.8×	0.051	SMARCA4, ACTL6A
MITF-M-regulated melanocyte development	2	16.3×	0.051	SMARCA4, ACTL6A
Signaling by Ligand-Responsive EGFR Variants in Cancer	1	135.9×	0.056	SOS1
Signaling by NTRK2 (TRKB)	1	116.5×	0.056	SOS1
Signaling by PDGFR in disease	1	116.5×	0.056	SOS1
SOS-mediated signalling	1	102.0×	0.056	SOS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
adult heart development	3	225.7×	8e-05	CHD7, NKX2-5, MYH6
atrioventricular node cell fate commitment	2	1053.2×	1e-04	TBX5, NKX2-5
bundle of His development	2	526.6×	3e-04	TBX5, NKX2-5
positive regulation of cardioblast differentiation	2	526.6×	3e-04	TBX5, NKX2-5
atrioventricular node cell development	2	526.6×	3e-04	TBX5, NKX2-5
cardiac muscle contraction	3	75.2×	4e-04	NKX2-5, DMD, MYH6
atrial septum morphogenesis	2	162.0×	0.003	TBX5, NKX2-5
cardiac septum morphogenesis	2	150.5×	0.003	CHD7, NKX2-5
ventricular trabecula myocardium morphogenesis	2	131.7×	0.003	CHD7, NKX2-5
regulation of DNA-templated transcription	5	9.9×	0.003	SETBP1, CHD7, ACTL6A, NKX2-5, MN1
neural retina development	2	117.0×	0.004	SMARCA4, ACTL6A
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	2	84.3×	0.006	CHD7, DMD
regulation of G0 to G1 transition	2	84.3×	0.006	SMARCA4, ACTL6A
cardiac muscle cell development	2	78.0×	0.007	NKX2-5, MYH6
regulation of nucleotide-excision repair	2	75.2×	0.007	SMARCA4, ACTL6A
cardiac muscle cell proliferation	2	72.6×	0.007	TBX5, NKX2-5
regulation of mitotic metaphase/anaphase transition	2	62.0×	0.009	SMARCA4, ACTL6A
Purkinje myocyte differentiation	1	1053.2×	0.009	NKX2-5
right ventricular compact myocardium morphogenesis	1	1053.2×	0.009	CHD7
septum secundum development	1	1053.2×	0.009	NKX2-5
visceral muscle development	1	1053.2×	0.009	MYH6
tonic smooth muscle contraction	1	1053.2×	0.009	MYLK
cell migration involved in coronary vasculogenesis	1	1053.2×	0.009	TBX5
negative regulation of neuroblast migration	1	1053.2×	0.009	ABCC8
regulation of muscle system process	1	1053.2×	0.009	DMD
regulation of cellular response to growth factor stimulus	1	1053.2×	0.009	DMD
positive regulation of uterine smooth muscle relaxation	1	1053.2×	0.009	ABCC8
positive regulation of cardiac conduction	1	1053.2×	0.009	TBX5
regulation of heart rate	2	58.5×	0.009	DMD, MYH6
positive regulation of T cell differentiation	2	56.9×	0.009	SMARCA4, ACTL6A

Therapeutics

Drugs indicated for this disease

0 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Bosentan	Phase 3 (in late-stage trials)
Dexmedetomidine	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 6 · Undrugged: 11

Druggability breadth: 12 of 17 evidence-associated genes (71%) 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
SOS1	IDARUBICIN
HDAC8	CELECOXIB
ABCC8	REPAGLINIDE
MYLK	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HDAC8	37	4
MYLK	28	4
ABCC8	6	4
SOS1	5	4
SMARCA4	2	2
ACTL6A	1	2
MYH6	0	0
TBX5	0	0
CYFIP1	0	0
SETBP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	SOS1
ADAGRASIB	4	SOS1
CELECOXIB	4	HDAC8
PHENYLBUTANOIC ACID	4	HDAC8
SODIUM PHENYLBUTYRATE	4	HDAC8
ROMIDEPSIN	4	HDAC8
BELINOSTAT	4	HDAC8
PANOBINOSTAT	4	HDAC8
VORINOSTAT	4	HDAC8
GIVINOSTAT	4	HDAC8
DAUNORUBICIN	4	HDAC8
BORTEZOMIB	4	HDAC8
BENDAMUSTINE	4	HDAC8
REPAGLINIDE	4	ABCC8
DIAZOXIDE	4	ABCC8
GLYBURIDE	4	ABCC8
PONATINIB	4	MYLK
AFATINIB	4	MYLK
FEDRATINIB	4	MYLK
RUXOLITINIB	4	MYLK
NIFEDIPINE	4	MYLK
BOSUTINIB	4	MYLK
GILTERITINIB	4	MYLK
TOVORAFENIB	4	MYLK
NINTEDANIB	4	MYLK
SUNITINIB	4	MYLK
DASATINIB	4	MYLK
QUIZARTINIB	4	MYLK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
HDAC8	2,631	Binding:2599, ADMET:25, Functional:6, Toxicity:1
SOS1	421	Binding:409, Functional:12
MYLK	303	Binding:303
SMARCA4	230	Binding:207, ADMET:12, Functional:11
ABCC8	84	Functional:52, Binding:32
CYFIP1	7	Binding:7
ACTL6A	7	Binding:7
HUWE1	4	Binding:3, Functional:1
CUL9	2	Binding:2
TBX5	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HDAC8	3.5.1.98	histone deacetylase
HUWE1	2.3.2.26	HECT-type E3 ubiquitin transferase
MYLK	2.7.11.18	myosin-light-chain kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SMARCA4	230
SOS1	421
HDAC8	2,631
MYLK	303

Pharmacogenomics

Cohort genes with a PharmGKB record: 17; 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)
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	SOS1
ADAGRASIB	4	SOS1
CELECOXIB	4	HDAC8
PHENYLBUTANOIC ACID	4	HDAC8
SODIUM PHENYLBUTYRATE	4	HDAC8
ROMIDEPSIN	4	HDAC8
BELINOSTAT	4	HDAC8
PANOBINOSTAT	4	HDAC8
VORINOSTAT	4	HDAC8
GIVINOSTAT	4	HDAC8
DAUNORUBICIN	4	HDAC8
BORTEZOMIB	4	HDAC8
BENDAMUSTINE	4	HDAC8
REPAGLINIDE	4	ABCC8
DIAZOXIDE	4	ABCC8
GLYBURIDE	4	ABCC8
PONATINIB	4	MYLK
AFATINIB	4	MYLK
FEDRATINIB	4	MYLK
RUXOLITINIB	4	MYLK
NIFEDIPINE	4	MYLK
BOSUTINIB	4	MYLK
GILTERITINIB	4	MYLK
TOVORAFENIB	4	MYLK
NINTEDANIB	4	MYLK
SUNITINIB	4	MYLK
DASATINIB	4	MYLK
QUIZARTINIB	4	MYLK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	SOS1, HDAC8, ABCC8, MYLK
B	Phased (≥1) drug, not yet approved	2	SMARCA4, ACTL6A
C	Druggable family + PDB, no drug	1	HUWE1
D	Druggable family + AlphaFold only, no drug	1	DIPK1A
E	Difficult family or no structure, no drug	9	MYH6, TBX5, CYFIP1, SETBP1, CUL9, CHD7, NKX2-5, DMD, MN1

Undrugged target profiles

11 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MYH6	0	—
TBX5	1	—
CYFIP1	7	—
SETBP1	0	—
CUL9	2	—
CHD7	0	—
NKX2-5	0	—
DMD	0	—
HUWE1	4	—
DIPK1A	0	—
MN1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 99.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	77
PHASE2	7
PHASE4	5
PHASE3	3
PHASE2/PHASE3	2
PHASE1/PHASE2	2
PHASE1	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06631534	PHASE4	RECRUITING	Effect of Dexmedetomidine Supplementation to General Anaesthesia in Paediatric Transcatheter Closure of Atrial Septal Defect
NCT07054541	PHASE4	NOT_YET_RECRUITING	A Novel Echocardiography-Guided Strategy for Percutateous Closure of Atrial Septal Defect Assisted by PannaWire
NCT07226739	PHASE4	NOT_YET_RECRUITING	Comprehensive Toileting Program
NCT01536717	PHASE4	SUSPENDED	Comparison of the Local Anaesthetics Articaine and Bupivacaine in Treatment of Acute Sternum Pain After Heart Surgery
NCT05688670	PHASE4	COMPLETED	Regional Anesthesia Following Pediatric Cardiac Surgery
NCT06678685	PHASE2/PHASE3	RECRUITING	Spironolactone Improved Children With Gene Mutations Related to NCOR
NCT00480740	PHASE3	COMPLETED	The Pharmacology and Hemodynamics of Dexmedetomidine in Children With Congenital Heart Disease
NCT01773252	PHASE3	TERMINATED	Right to Left Cardiac Shunt Detection
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03204786	PHASE2/PHASE3	COMPLETED	Intranasal Vasopressin Treatment in Children With Autism
NCT07303907	PHASE2	RECRUITING	A Phase 2A Trial of DT402 for Autism Spectrum Disorder
NCT07304440	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Adia MED of Winter Park LLC Autism Spectrum Disorder Research Study
NCT01120964	PHASE1/PHASE2	COMPLETED	Intravenous L-Citrulline to Treat Children Undergoing Heart Bypass Surgery : Revised Protocol
NCT01183221	PHASE2	COMPLETED	The Effects of Oxytocin on Complex Social Cognition in Autism Spectrum Disorders
NCT02847182	PHASE2	COMPLETED	Cord Blood Infusion for Children With Autism Spectrum Disorder
NCT03243552	PHASE2	UNKNOWN	Proof of Mechanism Study for the Treatment of Social Anhedonia in ASD
NCT03829878	PHASE2	WITHDRAWN	Efficacy, Safety, and Tolerability Study of Oral Full-Spectrum MicrobiotaTM (CP101) in Subjects With Autism Spectrum Disorder and Associated GI Symptoms (SPROUT)
NCT03900923	PHASE2	COMPLETED	Cannabidiol for ASD Open Trial
NCT05733390	PHASE2	WITHDRAWN	A Study of JZP541 in Adults With Irritability Associated With Autism Spectrum Disorder
NCT03099239	PHASE1	COMPLETED	hCT-MSCs for Children With Autism Spectrum Disorder (ASD)
NCT03189134	PHASE1	COMPLETED	Utilization of Confocal Microscopy During Cardiac Surgery
NCT06298344	EARLY_PHASE1	COMPLETED	The Role of Thiamine After Transcatheter Closure in Children With Left-to-Right Shunt Congenital Heart Disease
NCT02097758	Not specified	RECRUITING	Efficacy of Three Dimensional Transesophageal Echocardiography for Percutaneous Device Closure in Atrial Septal Defect
NCT02461446	Not specified	RECRUITING	Natural History Study of Individuals With Autism and Germline Heterozygous PTEN Mutations
NCT04288596	Not specified	NOT_YET_RECRUITING	Canadian Adult Congenital Heart Disease Intervention Registry
NCT04899544	Not specified	RECRUITING	Trial of Center-Based vs. In-Home Pivotal Response Treatment (PRT) in Autism
NCT05194254	Not specified	RECRUITING	MRI-Eye Tracking Pairing, a Tool for Assessing Social Cognition in Children With ASD
NCT05887700	Not specified	RECRUITING	Lifetech CeraFlex™ ASD Closure System Post-Market Clinical Follow-Up
NCT06012903	Not specified	RECRUITING	Lower Urinary Tract Symptoms and School Functioning in Children
NCT06236776	Not specified	NOT_YET_RECRUITING	AWARE Registry: Wearable ECG in Structural Heart Interventions
NCT06344494	Not specified	NOT_YET_RECRUITING	Cardiac Interventional ICE Imaging Trial
NCT06347276	Not specified	RECRUITING	Cerebral Microembolization Associated With PFO Closure
NCT06598605	Not specified	ACTIVE_NOT_RECRUITING	An Intervention Program to Improve Emotion Regulation Among Parents of Children with ASD
NCT06670040	Not specified	ACTIVE_NOT_RECRUITING	Theta Burst Stimulation for Refractory Depression in Autism Spectrum Disorder
NCT06700174	Not specified	RECRUITING	Lifetech AcuMark™ Sizing Balloon Post-Market Clinical Follow-up Study
NCT06761807	Not specified	NOT_YET_RECRUITING	Electrocardiographic and Electrophysiologic Changes After Percutaneous Closure of Atrial Septal Defect
NCT06849635	Not specified	RECRUITING	Cera™ ASD Occluder Post-Market Clinical Follow-Up Study
NCT07064538	Not specified	ACTIVE_NOT_RECRUITING	Effects of Neuralli® MP on Self-Defined Outcomes in Adults With Autistic Traits
NCT07259044	Not specified	NOT_YET_RECRUITING	Testing Scalable Caregiver Interventions for Autism
NCT07292896	Not specified	NOT_YET_RECRUITING	A Multicenter Study on the Normal Reference Range and Clinical Significance of the Right Atrioventricular Coupling Index Assessed by Artificial Intelligence-Based Three-Dimensional Echocardiography

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
THIAMINE ION	4	2
ARTICAINE	4	1
FLUORESCEIN SODIUM	4	1
GLYCERIN	4	1
OXYTOCIN	4	1
SODIUM CHLORIDE	4	1
GLUTATHIONE	3	1
L-CITRULLINE	3	1
CHEMBL4303358	0	1