Atypical coarctation of aorta

Summary

Atypical coarctation of aorta (MONDO:0015446) is a disease with 4 cohort genes. The dominant Reactome pathway is Diseases of signal transduction by growth factor receptors and second messengers (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Cohort genes: 4
• ClinVar variants: 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated
Prevalence at birth	1-9 / 1 000 000	0.17	Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	atypical coarctation of aorta
Mondo ID	MONDO:0015446
Orphanet	1456
ICD-11	480830042
SNOMED CT	471268000
UMLS	C3496579
MedGen	758831
GARD	0018723
Is cancer (heuristic)	no

Also known as: coarctation of the abdominal aorta · mid-aortic dysplastic syndrome · mid-aortic syndrome · Midaortic syndrome · middle aortic syndrome

Data availability: 11 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › aorta coarctation › atypical coarctation of aorta

Related subtypes (1): autosomal dominant coarctation of aorta

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

11 retrieved; paginated sample, class counts are floors:

3 pathogenic, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
213529	NM_000214.3(JAG1):c.439+1G>A	JAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
213539	NM_000214.3(JAG1):c.2698C>T (p.Arg900Ter)	JAG1	Pathogenic	criteria provided, multiple submitters, no conflicts
439997	NM_001042492.3(NF1):c.4577+1G>A	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
641476	NM_001042492.3(NF1):c.1260+5G>A	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68323	NM_001042492.3(NF1):c.2540T>C (p.Leu847Pro)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
684684	NM_005257.6(GATA6):c.1532C>G (p.Ser511Cys)	GATA6	Likely pathogenic	no assertion criteria provided
684681	NM_000214.3(JAG1):c.1313G>A (p.Cys438Tyr)	JAG1	Likely pathogenic	no assertion criteria provided
684682	NM_000214.3(JAG1):c.2092_2093insG (p.Lys698fs)	JAG1	Likely pathogenic	no assertion criteria provided
141982	NM_001042492.3(NF1):c.1166A>G (p.His389Arg)	NF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
684683	NM_001256071.3(RNF213):c.6169G>A (p.Asp2057Asn)	RNF213	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
237573	NM_001042492.3(NF1):c.5227G>C (p.Ala1743Pro)	NF1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 21 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RNF213	Orphanet:2573	Moyamoya disease
GATA6	Orphanet:2140	Congenital diaphragmatic hernia
GATA6	Orphanet:2255	Pancreatic hypoplasia-diabetes-congenital heart disease syndrome
GATA6	Orphanet:3303	Tetralogy of Fallot
GATA6	Orphanet:334	Hereditary atrial fibrillation
GATA6	Orphanet:665044	Common arterial trunk with aortic dominance
GATA6	Orphanet:665058	Common arterial trunk with pulmonary dominance and interrupted aortic arch
GATA6	Orphanet:99067	Complete atrioventricular septal defect with ventricular hypoplasia
GATA6	Orphanet:99103	Atrial septal defect, ostium secundum type
JAG1	Orphanet:261600	Alagille syndrome due to 20p12 microdeletion
JAG1	Orphanet:261619	Alagille syndrome due to a JAG1 point mutation
JAG1	Orphanet:3303	Tetralogy of Fallot
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma

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
RNF213	HGNC:14539	ENSG00000173821	Q63HN8	E3 ubiquitin-protein ligase RNF213	clinvar
GATA6	HGNC:4174	ENSG00000141448	Q92908	Transcription factor GATA-6	clinvar
JAG1	HGNC:6188	ENSG00000101384	P78504	Protein jagged-1	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNF213	E3 ubiquitin-protein ligase RNF213	Atypical E3 ubiquitin ligase that can catalyze ubiquitination of both proteins and lipids, and which is involved in various processes, such as lipid metabolism, angiogenesis and cell-autonomous immunity.
GATA6	Transcription factor GATA-6	Transcriptional activator.
JAG1	Protein jagged-1	Ligand for multiple Notch receptors and involved in the mediation of Notch signaling.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.

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)
RNF213	Transcription factor	no		Znf_RING, AAA+_ATPase, Znf_RING/FYVE/PHD
GATA6	Transcription factor	no		Znf_GATA, GATA_N, Znf_NHR/GATA
JAG1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, VWF_dom
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot

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
granulocyte	1
metanephros cortex	1
pancreatic ductal cell	1
germinal epithelium of ovary	1
jejunal mucosa	1
parietal pleura	1
blood vessel layer	1
skin of hip	1
upper leg skin	1
adrenal tissue	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNF213	252	ubiquitous	marker	granulocyte, metanephros cortex, pancreatic ductal cell
GATA6	204	ubiquitous	marker	germinal epithelium of ovary, parietal pleura, jejunal mucosa
JAG1	297	ubiquitous	marker	upper leg skin, skin of hip, blood vessel layer
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NF1	5,540
JAG1	4,405
RNF213	2,368
GATA6	49

Intra-cohort edges

A	B	Sources
NF1	RNF213	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NF1	P21359	26
JAG1	P78504	7
RNF213	Q63HN8	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GATA6	Q92908	53.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 57. 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
Diseases of signal transduction by growth factor receptors and second messengers	3	42.6×	0.001	RNF213, JAG1, NF1
Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	713.8×	0.019	JAG1
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	407.9×	0.019	JAG1
RAS signaling downstream of NF1 loss-of-function variants	1	407.9×	0.019	NF1
Suppression of apoptosis	1	407.9×	0.019	RNF213
Response of Mtb to phagocytosis	1	356.9×	0.019	RNF213
Signaling by NOTCH1 HD Domain Mutants in Cancer	1	317.2×	0.019	JAG1
POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation	1	285.5×	0.019	GATA6
Infection with Mycobacterium tuberculosis	1	285.5×	0.019	RNF213
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	259.6×	0.019	JAG1
Nephron development	1	219.6×	0.019	JAG1
RUNX3 regulates NOTCH signaling	1	203.9×	0.019	JAG1
Kidney development	1	203.9×	0.019	JAG1
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	190.3×	0.019	JAG1
Signaling by NOTCH2	1	178.4×	0.019	JAG1
Formation of definitive endoderm	1	178.4×	0.019	GATA6
Disease	3	9.8×	0.019	RNF213, JAG1, NF1
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	150.3×	0.021	GATA6
Signaling by NOTCH3	1	129.8×	0.021	JAG1
Signaling by NOTCH4	1	124.1×	0.021	JAG1
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	119.0×	0.021	JAG1
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	109.8×	0.021	JAG1
Cardiogenesis	1	105.7×	0.021	GATA6
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	102.0×	0.021	JAG1
Signaling by NOTCH1 in Cancer	1	102.0×	0.021	JAG1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	102.0×	0.021	JAG1
Surfactant metabolism	1	92.1×	0.022	GATA6
Signaling by NOTCH1	1	89.2×	0.022	JAG1
Activated NOTCH1 Transmits Signal to the Nucleus	1	89.2×	0.022	JAG1
Bacterial Infection Pathways	1	84.0×	0.023	RNF213

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
negative regulation of cell-matrix adhesion	2	443.5×	0.001	JAG1, NF1
angiogenesis	3	46.8×	0.002	RNF213, JAG1, NF1
negative regulation of transforming growth factor beta2 production	1	4213.0×	0.004	GATA6
positive regulation of mast cell apoptotic process	1	4213.0×	0.004	NF1
tube morphogenesis	1	4213.0×	0.004	GATA6
regulation of glial cell differentiation	1	4213.0×	0.004	NF1
endocardial cushion cell development	1	4213.0×	0.004	JAG1
observational learning	1	4213.0×	0.004	NF1
lipid ubiquitination	1	4213.0×	0.004	RNF213
negative regulation of sebum secreting cell proliferation	1	4213.0×	0.004	GATA6
liver development	2	110.9×	0.004	GATA6, NF1
regulation of antimicrobial humoral response	1	2106.5×	0.005	GATA6
endodermal cell fate determination	1	2106.5×	0.005	GATA6
gamma-aminobutyric acid secretion, neurotransmission	1	2106.5×	0.005	NF1
loop of Henle development	1	2106.5×	0.005	JAG1
sebaceous gland cell differentiation	1	1404.3×	0.005	GATA6
Schwann cell proliferation	1	1404.3×	0.005	NF1
forebrain astrocyte development	1	1404.3×	0.005	NF1
Schwann cell migration	1	1404.3×	0.005	NF1
cardiac neural crest cell development involved in outflow tract morphogenesis	1	1404.3×	0.005	JAG1
glutamate secretion, neurotransmission	1	1404.3×	0.005	NF1
negative regulation of mast cell proliferation	1	1404.3×	0.005	NF1
distal tubule development	1	1404.3×	0.005	JAG1
positive regulation of cardiac muscle myoblast proliferation	1	1404.3×	0.005	GATA6
negative regulation of Schwann cell migration	1	1404.3×	0.005	NF1
vascular associated smooth muscle cell migration	1	1404.3×	0.005	NF1
negative regulation of cell migration	2	55.8×	0.005	JAG1, NF1
inhibition of neuroepithelial cell differentiation	1	1053.2×	0.005	JAG1
mast cell apoptotic process	1	1053.2×	0.005	NF1
negative regulation of Rac protein signal transduction	1	1053.2×	0.005	NF1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RNF213	0	0
GATA6	0	0
JAG1	0	0
NF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RNF213	1	Binding:1
JAG1	1	Binding:1

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	RNF213, GATA6, JAG1, NF1

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)
RNF213	1	—
GATA6	0	—
JAG1	1	—
NF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.