Aortic arch interruption

Summary

Aortic arch interruption (MONDO:0009010) is a disease with 1 cohort gene.

At a glance

• Prevalence: Unknown (Europe)
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 32

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.3	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0030148	Heart murmur	Very frequent (80-99%)
HP:0032092	Left ventricular outflow tract obstruction	Very frequent (80-99%)
HP:0032554	Absent pulse	Very frequent (80-99%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0000961	Cyanosis	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0001629	Ventricular septal defect	Frequent (30-79%)
HP:0001635	Congestive heart failure	Frequent (30-79%)
HP:0001712	Left ventricular hypertrophy	Frequent (30-79%)
HP:0002098	Respiratory distress	Frequent (30-79%)
HP:0002789	Tachypnea	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0010741	Pedal edema	Frequent (30-79%)
HP:0020142	Blood pressure substantially higher in arms than legs	Frequent (30-79%)
HP:0030973	Postexertional malaise	Frequent (30-79%)
HP:0031273	Shock	Frequent (30-79%)
HP:0031664	Systolic heart murmur	Frequent (30-79%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001647	Bicuspid aortic valve	Occasional (5-29%)
HP:0001659	Aortic regurgitation	Occasional (5-29%)
HP:0001660	Truncus arteriosus	Occasional (5-29%)
HP:0001669	Transposition of the great arteries	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0002875	Exertional dyspnea	Occasional (5-29%)
HP:0004417	Intermittent claudication	Occasional (5-29%)
HP:0005180	Tricuspid regurgitation	Occasional (5-29%)
HP:0011604	Aortopulmonary window	Occasional (5-29%)
HP:0011712	Right bundle branch block	Occasional (5-29%)
HP:0031784	Abnormal ascending aorta morphology	Occasional (5-29%)
HP:0001719	Double outlet right ventricle	Very rare (<1-4%)
HP:0001750	Single ventricle	Very rare (<1-4%)
HP:0010883	Aortic valve atresia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	aortic arch interruption
Mondo ID	MONDO:0009010
Orphanet	2299
ICD-10-CM	Q25.21
ICD-11	1769930414
UMLS	C0152419
MedGen	57773
GARD	0000740
MedDRA	10022599
Is cancer (heuristic)	no

Data availability: 1 ClinVar variant.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › congenital anomaly of cardiovascular system › congenital heart malformation › congenital anomaly of the great arteries › aortic arch interruption

Related subtypes (14): aortic arch defects, idiopathic pulmonary artery dilatation, scimitar syndrome, fixed subaortic stenosis, congenital pulmonary veins atresia or stenosis, congenital pulmonary valve stenosis, aorto-ventricular tunnel, aneurysm or dilatation of ascending aorta, premature closure of the arterial duct, absence of the pulmonary artery, congenital patent ductus arteriosus aneurysm, pulmonary artery hypoplasia, pulmonary branch stenosis, primary pulmonary vein stenosis

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

1 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
9008	NM_004387.4(NKX2-5):c.73C>T (p.Arg25Cys)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NKX2-5	HGNC:2488	ENSG00000183072	P52952	Homeobox protein Nkx-2.5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NKX2-5	Homeobox protein Nkx-2.5	Transcription factor required for the development of the heart and the spleen.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NKX2-5	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
cardiac atrium	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NKX2-5	98	broad	yes	apex of heart, right atrium auricular region, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NKX2-5	2,355

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NKX2-5	P52952	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 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	1	761.3×	0.002	NKX2-5
Physiological factors	1	671.8×	0.002	NKX2-5
Cardiogenesis	1	423.0×	0.002	NKX2-5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Purkinje myocyte differentiation	1	16852.0×	0.001	NKX2-5
septum secundum development	1	16852.0×	0.001	NKX2-5
right ventricular cardiac muscle tissue morphogenesis	1	8426.0×	0.001	NKX2-5
atrioventricular node cell fate commitment	1	8426.0×	0.001	NKX2-5
cardiac ventricle formation	1	5617.3×	0.001	NKX2-5
apoptotic process involved in heart morphogenesis	1	5617.3×	0.001	NKX2-5
proepicardium development	1	5617.3×	0.001	NKX2-5
pulmonary myocardium development	1	5617.3×	0.001	NKX2-5
ventricular cardiac myofibril assembly	1	5617.3×	0.001	NKX2-5
atrial cardiac muscle cell development	1	5617.3×	0.001	NKX2-5
bundle of His development	1	4213.0×	0.001	NKX2-5
atrial cardiac muscle tissue development	1	4213.0×	0.001	NKX2-5
positive regulation of cardioblast differentiation	1	4213.0×	0.001	NKX2-5
atrioventricular node cell development	1	4213.0×	0.001	NKX2-5
regulation of cardiac muscle cell proliferation	1	3370.4×	0.001	NKX2-5
atrioventricular node development	1	2808.7×	0.001	NKX2-5
embryonic heart tube left/right pattern formation	1	2808.7×	0.001	NKX2-5
positive regulation of heart contraction	1	2106.5×	0.002	NKX2-5
ventricular cardiac muscle cell development	1	1532.0×	0.002	NKX2-5
cardiac muscle tissue morphogenesis	1	1404.3×	0.002	NKX2-5
atrial septum morphogenesis	1	1296.3×	0.002	NKX2-5
adult heart development	1	1203.7×	0.002	NKX2-5
cardiac septum morphogenesis	1	1203.7×	0.002	NKX2-5
negative regulation of epithelial cell apoptotic process	1	1203.7×	0.002	NKX2-5
negative regulation of myotube differentiation	1	1123.5×	0.002	NKX2-5
heart trabecula formation	1	1123.5×	0.002	NKX2-5
cardiac conduction system development	1	1053.2×	0.002	NKX2-5
ventricular trabecula myocardium morphogenesis	1	1053.2×	0.002	NKX2-5
regulation of cardiac muscle contraction	1	887.0×	0.002	NKX2-5
positive regulation of sodium ion transport	1	842.6×	0.002	NKX2-5

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
NKX2-5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	NKX2-5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NKX2-5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.