NKX2.5-related congenital, conduction and myopathic heart disease

Summary

NKX2.5-related congenital, conduction and myopathic heart disease (MONDO:0800441) is a disease caused by NKX2-5 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: NKX2-5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	NKX2.5-related congenital, conduction and myopathic heart disease
Mondo ID	MONDO:0800441
GARD	0026559
Is cancer (heuristic)	no

Also known as: NKX2-5-related congenital, conduction and myopathic heart disease

Data availability: 3 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › NKX2.5-related congenital, conduction and myopathic heart disease

Related subtypes (9): short QT syndrome, atrioventricular block, sinoatrial node disorder, Wolff-Parkinson-White syndrome, postural orthostatic tachycardia syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, progressive familial heart block, sinoatrial block

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

3 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4531982	NM_004387.4(NKX2-5):c.481_482del (p.Arg161fs)	NKX2-5	Pathogenic	criteria provided, single submitter
4531981	NM_004387.4(NKX2-5):c.552C>G (p.Ile184Met)	NKX2-5	Likely pathogenic	criteria provided, single submitter
2419762	NM_004387.4(NKX2-5):c.494C>G (p.Ala165Gly)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 11 · 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
NKX2-5	Definitive	Semidominant	conotruncal heart malformations	17

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	gencc,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.