Familial bicuspid aortic valve

Summary

Familial bicuspid aortic valve (MONDO:0007194) is a disease with 4 cohort genes.

At a glance

• Cohort genes: 4
• Phenotypes (HPO): 12

Clinical features

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0001647	Bicuspid aortic valve	Obligate (100%)
HP:0001650	Aortic valve stenosis	Very frequent (80-99%)
HP:0001659	Aortic regurgitation	Very frequent (80-99%)
HP:0001680	Coarctation of aorta	Very frequent (80-99%)
HP:0004380	Aortic valve calcification	Very frequent (80-99%)
HP:0004962	Thoracic aorta calcification	Very frequent (80-99%)
HP:0030148	Heart murmur	Very frequent (80-99%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0005113	Dilatation of the aortic arch	Frequent (30-79%)
HP:0004383	Hypoplastic left heart	Very rare (<1-4%)
HP:0004933	Ascending aortic dissection	Very rare (<1-4%)
HP:0011103	Abnormal left ventricular outflow tract morphology	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	familial bicuspid aortic valve
Mondo ID	MONDO:0007194
OMIM	109730
Orphanet	402075
DOID	DOID:0080332
UMLS	C4749284
MedGen	1670287
GARD	0017670
Is cancer (heuristic)	no

Also known as: aortic valve disease 1 · aortic valve disease type 1 · AOVD1 · familial BAV

Data availability: 4 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart valve disorder › aortic valve disorder › familial bicuspid aortic valve

Related subtypes (4): aortic valve calcification, aortic valve insufficiency, aortic valve prolapse, aortic valve stenosis

Subtypes (3): aortic valve disease 2, aortic valve disease 1, aortic valve disease 3

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 47 · Orphanet: 17 · 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
NOTCH1	Strong	Autosomal dominant	aortic valve disease 1	9
SMAD6	Moderate	Autosomal dominant	aortic valve disease 2	14
GATA5	Supportive	Autosomal dominant	familial bicuspid aortic valve	7
NKX2-5	Supportive	Autosomal dominant	familial bicuspid aortic valve	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GATA5	Orphanet:3303	Tetralogy of Fallot
GATA5	Orphanet:334	Hereditary atrial fibrillation
GATA5	Orphanet:402075	Familial bicuspid aortic valve
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
SMAD6	Orphanet:402075	Familial bicuspid aortic valve
NOTCH1	Orphanet:402075	Familial bicuspid aortic valve
NOTCH1	Orphanet:974	Adams-Oliver syndrome

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
GATA5	HGNC:15802	ENSG00000130700	Q9BWX5	Transcription factor GATA-5	gencc
NKX2-5	HGNC:2488	ENSG00000183072	P52952	Homeobox protein Nkx-2.5	gencc
SMAD6	HGNC:6772	ENSG00000137834	O43541	SMAD family member 6	gencc
NOTCH1	HGNC:7881	ENSG00000148400	P46531	Neurogenic locus notch homolog protein 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GATA5	Transcription factor GATA-5	Transcription factor required during cardiovascular development.
NKX2-5	Homeobox protein Nkx-2.5	Transcription factor required for the development of the heart and the spleen.
SMAD6	SMAD family member 6	Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators.
NOTCH1	Neurogenic locus notch homolog protein 1	Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.

Protein-family classification

Druggable: 0 · Difficult: 3 · Unknown: 1 · 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×	0.223
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GATA5	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA
NKX2-5	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
SMAD6	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
NOTCH1	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

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
ileal mucosa	1
jejunal mucosa	1
left uterine tube	1
apex of heart	1
cardiac atrium	1
right atrium auricular region	1
metanephric glomerulus	1
renal glomerulus	1
right lung	1
colonic epithelium	1
ventricular zone	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GATA5	106	broad	yes	ileal mucosa, left uterine tube, jejunal mucosa
NKX2-5	98	broad	yes	apex of heart, right atrium auricular region, cardiac atrium
SMAD6	277	ubiquitous	marker	right lung, renal glomerulus, metanephric glomerulus
NOTCH1	272	ubiquitous	marker	ventricular zone, colonic epithelium, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH1	7,411
GATA5	2,434
NKX2-5	2,355
SMAD6	2,006

Intra-cohort edges

A	B	Sources
GATA5	NKX2-5	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH1	P46531	29
NKX2-5	P52952	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SMAD6	O43541	72.34
GATA5	Q9BWX5	59.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling	1	571.0×	0.016	NOTCH1
Defective LFNG causes SCDO3	1	571.0×	0.016	NOTCH1
Pre-NOTCH Processing in the Endoplasmic Reticulum	1	475.8×	0.016	NOTCH1
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	407.9×	0.016	NOTCH1
Regulation of NFE2L2 gene expression	1	356.9×	0.016	NOTCH1
NFE2L2 regulating tumorigenic genes	1	237.9×	0.016	NOTCH1
RUNX2 regulates bone development	1	203.9×	0.016	SMAD6
RUNX3 regulates NOTCH signaling	1	203.9×	0.016	NOTCH1
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	190.3×	0.016	NKX2-5
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	190.3×	0.016	NOTCH1
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	178.4×	0.016	NOTCH1
Physiological factors	1	167.9×	0.016	NKX2-5
Pre-NOTCH Processing in Golgi	1	158.6×	0.016	NOTCH1
MECP2 regulates neuronal receptors and channels	1	150.3×	0.016	NOTCH1
NOTCH4 Intracellular Domain Regulates Transcription	1	142.8×	0.016	NOTCH1
NOTCH3 Intracellular Domain Regulates Transcription	1	109.8×	0.018	NOTCH1
Cardiogenesis	1	105.7×	0.018	NKX2-5
Notch-HLH transcription pathway	1	102.0×	0.018	NOTCH1
Formation of paraxial mesoderm	1	102.0×	0.018	NOTCH1
Signaling by BMP	1	89.2×	0.019	SMAD6
Activated NOTCH1 Transmits Signal to the Nucleus	1	89.2×	0.019	NOTCH1
Nuclear events stimulated by ALK signaling in cancer	1	81.6×	0.019	NOTCH1
Transcriptional regulation by RUNX2	1	63.4×	0.024	SMAD6
NOTCH1 Intracellular Domain Regulates Transcription	1	59.5×	0.024	NOTCH1
Somitogenesis	1	58.3×	0.024	NOTCH1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	49.2×	0.026	NOTCH1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	49.2×	0.026	NOTCH1
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	36.6×	0.034	NOTCH1
Pre-NOTCH Transcription and Translation	1	30.7×	0.039	NOTCH1
Signaling by TGFB family members	1	28.8×	0.040	SMAD6

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
aortic valve morphogenesis	4	432.1×	6e-09	GATA5, NKX2-5, SMAD6, NOTCH1
atrioventricular node development	2	1404.3×	7e-05	NKX2-5, NOTCH1
cardiac muscle tissue morphogenesis	2	702.2×	2e-04	NKX2-5, NOTCH1
cardiac septum morphogenesis	2	601.9×	2e-04	NKX2-5, NOTCH1
negative regulation of cardiac muscle hypertrophy	2	561.7×	2e-04	GATA5, NOTCH1
negative regulation of myotube differentiation	2	561.7×	2e-04	NKX2-5, NOTCH1
ventricular trabecula myocardium morphogenesis	2	526.6×	2e-04	NKX2-5, NOTCH1
pulmonary valve morphogenesis	2	468.1×	2e-04	SMAD6, NOTCH1
outflow tract septum morphogenesis	2	324.1×	3e-04	NKX2-5, SMAD6
negative regulation of ossification	2	312.1×	3e-04	SMAD6, NOTCH1
cardiac muscle cell proliferation	2	290.6×	4e-04	NKX2-5, NOTCH1
negative regulation of cardiac muscle cell apoptotic process	2	271.8×	4e-04	NKX2-5, NOTCH1
ventricular septum morphogenesis	2	216.1×	6e-04	NKX2-5, NOTCH1
positive regulation of Notch signaling pathway	2	175.5×	8e-04	GATA5, NOTCH1
epithelial cell proliferation	2	156.0×	9e-04	NKX2-5, NOTCH1
negative regulation of osteoblast differentiation	2	147.8×	9e-04	SMAD6, NOTCH1
negative regulation of BMP signaling pathway	2	145.3×	9e-04	SMAD6, NOTCH1
positive regulation of gene expression	3	29.1×	9e-04	GATA5, NKX2-5, NOTCH1
heart looping	2	133.8×	1e-03	NKX2-5, NOTCH1
positive regulation of epithelial cell proliferation	2	122.1×	0.001	NKX2-5, NOTCH1
Purkinje myocyte differentiation	1	4213.0×	0.002	NKX2-5
coronary sinus valve morphogenesis	1	4213.0×	0.002	NOTCH1
Notch signaling pathway involved in regulation of secondary heart field cardioblast proliferation	1	4213.0×	0.002	NOTCH1
septum secundum development	1	4213.0×	0.002	NKX2-5
foregut morphogenesis	1	4213.0×	0.002	NOTCH1
regulation of epithelial cell proliferation involved in prostate gland development	1	4213.0×	0.002	NOTCH1
venous endothelial cell differentiation	1	4213.0×	0.002	NOTCH1
positive regulation of cardiac endothelial to mesenchymal transition	1	4213.0×	0.002	GATA5
endocardium morphogenesis	1	2106.5×	0.003	NOTCH1
coronary vein morphogenesis	1	2106.5×	0.003	NOTCH1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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
NOTCH1	1	2
GATA5	0	0
NKX2-5	0	0
SMAD6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VAREGACESTAT	2	NOTCH1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOTCH1	23	Binding:19, ADMET:4

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

1 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)
VAREGACESTAT	2	NOTCH1

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	NOTCH1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	GATA5, NKX2-5, SMAD6

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)
GATA5	0	—
NKX2-5	0	—
SMAD6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.