Hypothyroidism, congenital, nongoitrous, 5

Summary

Hypothyroidism, congenital, nongoitrous, 5 (MONDO:0009154) is a disease caused by NKX2-5 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: NKX2-5 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 42

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypothyroidism, congenital, nongoitrous, 5
Mondo ID	MONDO:0009154
MeSH	C567123
OMIM	225250
DOID	DOID:0070125
UMLS	C2673630
MedGen	388687
GARD	0015165
Is cancer (heuristic)	no

Also known as: CHNG5 · hypothyroidism, congenital nongoitrous, 5 · hypothyroidism, congenital, nongoitrous caused by mutation in NKX2-5 · hypothyroidism, congenital, nongoitrous, 5 · hypothyroidism, congenital, nongoitrous, type 5 · NKX2-5 hypothyroidism, congenital, nongoitrous

Data availability: 42 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hypothyroidism, congenital, nongoitrous › hypothyroidism, congenital, nongoitrous, 5

Related subtypes (8): isolated thyroid-stimulating hormone deficiency, hypothyroidism due to TSH receptor mutations, congenital nongoitrous hypothyroidism 3, congenital nongoitrous hypothyroidism 6, hypothyroidism, congenital, nongoitrous, 2, hypothyroidism, congenital, nongoitrous, 8, hypothyroidism, congenital, nongoitrous, 9, hypothyroidism, congenital, nongoitrous, 7

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

42 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 11 conflicting classifications of pathogenicity, 4 likely benign, 2 benign/likely benign, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
159257	NM_004387.4(NKX2-5):c.783del (p.Ala262fs)	NKX2-5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320188	NM_004387.4(NKX2-5):c.335-204del	NKX2-5	Likely pathogenic	criteria provided, single submitter
1019319	NM_004387.4(NKX2-5):c.178G>C (p.Glu60Gln)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1021433	NM_004387.4(NKX2-5):c.169G>T (p.Ala57Ser)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1377875	NM_004387.4(NKX2-5):c.510G>C (p.Gln170His)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1439076	NM_004387.4(NKX2-5):c.370A>G (p.Lys124Glu)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
156161	NM_004387.4(NKX2-5):c.809G>A (p.Cys270Tyr)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372743	NM_004387.4(NKX2-5):c.356C>A (p.Ala119Glu)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
392351	NM_004387.4(NKX2-5):c.827C>G (p.Ala276Gly)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
505440	NM_004387.4(NKX2-5):c.111G>A (p.Leu37=)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
850796	NM_004387.4(NKX2-5):c.188C>T (p.Ala63Val)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9008	NM_004387.4(NKX2-5):c.73C>T (p.Arg25Cys)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
939551	NM_004387.4(NKX2-5):c.387C>A (p.Asn129Lys)	NKX2-5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1016187	NM_004387.4(NKX2-5):c.650G>A (p.Arg217Lys)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1021042	NM_004387.4(NKX2-5):c.521T>G (p.Val174Gly)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1022958	NM_004387.4(NKX2-5):c.248C>G (p.Ala83Gly)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1061973	NM_004387.4(NKX2-5):c.627GCC[7] (p.Pro213_Pro214dup)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1308506	NM_004387.4(NKX2-5):c.893G>A (p.Gly298Glu)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1437112	NM_004387.4(NKX2-5):c.494C>T (p.Ala165Val)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1513563	NM_004387.4(NKX2-5):c.763G>A (p.Ala255Thr)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
190835	NM_004387.4(NKX2-5):c.590G>C (p.Arg197Pro)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
283727	NM_004387.4(NKX2-5):c.769C>A (p.Pro257Thr)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
30115	NM_004387.4(NKX2-5):c.848C>A (p.Pro283Gln)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
410969	NM_004387.4(NKX2-5):c.865AAC[2] (p.Asn291del)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
468245	NM_004387.4(NKX2-5):c.65A>C (p.Gln22Pro)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
518495	NM_004387.4(NKX2-5):c.448G>A (p.Val150Ile)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
519318	NM_004387.4(NKX2-5):c.753C>G (p.Asn251Lys)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
520891	NM_004387.4(NKX2-5):c.890_891dup (p.Gly298fs)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
578898	NM_004387.4(NKX2-5):c.13C>T (p.Pro5Ser)	NKX2-5	Uncertain significance	criteria provided, multiple submitters, no conflicts
837477	NM_004387.4(NKX2-5):c.842C>A (p.Ala281Glu)	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	Autosomal dominant	hypothyroidism, congenital, nongoitrous, 5	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.