Hypothyroidism, congenital, nongoitrous, 2

Summary

Hypothyroidism, congenital, nongoitrous, 2 (MONDO:0024264) is a disease caused by PAX8 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: PAX8 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 128

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypothyroidism, congenital, nongoitrous, 2
Mondo ID	MONDO:0024264
MeSH	C566852
OMIM	218700
DOID	DOID:0070124
UMLS	C1869118
MedGen	358389
GARD	0025378
Is cancer (heuristic)	no

Also known as: CHNG2 · hypothyroidism, congenital, due to thyroid dysgenesis or hypoplasia · hypothyroidism, congenital, nongoitrous, 2

Data availability: 128 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, 2

Related subtypes (8): hypothyroidism, congenital, nongoitrous, 5, isolated thyroid-stimulating hormone deficiency, hypothyroidism due to TSH receptor mutations, congenital nongoitrous hypothyroidism 3, congenital nongoitrous hypothyroidism 6, 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

128 retrieved; paginated sample, class counts are floors:

72 uncertain significance, 18 conflicting classifications of pathogenicity, 10 benign, 9 likely pathogenic, 9 pathogenic, 5 benign/likely benign, 4 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13784	NM_003466.4(PAX8):c.92G>A (p.Arg31His)	PAX8	Pathogenic	criteria provided, single submitter
13785	NM_003466.4(PAX8):c.185T>G (p.Leu62Arg)	PAX8	Pathogenic	no assertion criteria provided
3894534	NM_003466.4(PAX8):c.191+1G>A	PAX8	Pathogenic	criteria provided, single submitter
915465	NM_003466.4(PAX8):c.457_458del (p.Leu153fs)	PAX8	Pathogenic	no assertion criteria provided
13783	NM_003466.4(PAX8):c.322C>T (p.Arg108Ter)	PAX8-AS1	Pathogenic	criteria provided, single submitter
13786	NM_003466.4(PAX8):c.170G>A (p.Cys57Tyr)	PAX8-AS1	Pathogenic	no assertion criteria provided
13787	NM_003466.4(PAX8):c.160A>G (p.Ser54Gly)	PAX8-AS1	Pathogenic	no assertion criteria provided
13788	NM_003466.4(PAX8):c.119A>C (p.Gln40Pro)	PAX8-AS1	Pathogenic	no assertion criteria provided
13789	NM_003466.4(PAX8):c.143C>T (p.Ser48Phe)	PAX8-AS1	Pathogenic	no assertion criteria provided
986916	NM_003466.4(PAX8):c.91C>T (p.Arg31Cys)	PAX8-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3062111	NM_003466.4(PAX8):c.205G>A (p.Gly69Ser)	PAX8	Likely pathogenic	criteria provided, single submitter
3776267	NM_003466.4(PAX8):c.898+1G>C	PAX8	Likely pathogenic	criteria provided, single submitter
4279554	NM_003466.4(PAX8):c.936dup (p.Glu313fs)	PAX8	Likely pathogenic	criteria provided, single submitter
436165	NM_003466.4(PAX8):c.160A>T (p.Ser54Cys)	PAX8	Likely pathogenic	criteria provided, single submitter
1328393	NM_003466.4(PAX8):c.237dup (p.Lys80fs)	PAX8-AS1	Likely pathogenic	no assertion criteria provided
3584291	NM_003466.4(PAX8):c.398G>A (p.Arg133Gln)	PAX8-AS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531763	NM_003466.4(PAX8):c.928G>T (p.Glu310Ter)	PAX8-AS1	Likely pathogenic	criteria provided, single submitter
872942	NM_003466.4(PAX8):c.203C>T (p.Thr68Ile)	PAX8-AS1	Likely pathogenic	criteria provided, single submitter
915464	NM_003466.4(PAX8):c.236C>T (p.Ser79Phe)	PAX8-AS1	Likely pathogenic	no assertion criteria provided
893211	NM_003466.4(PAX8):c.-63C>A	LOC108281110	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
714128	NM_003466.4(PAX8):c.704C>T (p.Pro235Leu)	LOC126806316	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1303477	NM_003466.4(PAX8):c.1109C>T (p.Thr370Met)	PAX8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259051	NM_003466.4(PAX8):c.898+11C>T	PAX8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330885	NM_003466.4(PAX8):c.1227C>G (p.Pro409=)	PAX8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330886	NM_003466.4(PAX8):c.1189+15G>A	PAX8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330890	NM_003466.4(PAX8):c.885C>T (p.Tyr295=)	PAX8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330893	NM_003466.4(PAX8):c.479-6C>T	PAX8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330895	NM_003466.4(PAX8):c.129G>A (p.Arg43=)	PAX8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
702769	NM_003466.4(PAX8):c.1087+4C>T	PAX8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
704396	NM_003466.4(PAX8):c.1116C>T (p.Pro372=)	PAX8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 8 · 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
PAX8	Definitive	Autosomal dominant	hypothyroidism, congenital, nongoitrous, 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PAX8	Orphanet:146	Differentiated thyroid carcinoma
PAX8	Orphanet:95712	Thyroid ectopia
PAX8	Orphanet:95713	Athyreosis
PAX8	Orphanet:95720	Thyroid hypoplasia
NKX2-1	Orphanet:1429	Benign hereditary chorea
NKX2-1	Orphanet:146	Differentiated thyroid carcinoma
NKX2-1	Orphanet:209905	Brain-lung-thyroid syndrome
NKX2-1	Orphanet:95713	Athyreosis

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PAX8	HGNC:8622	ENSG00000125618	Q06710	Paired box protein Pax-8	gencc,clinvar
NKX2-1	HGNC:11825	ENSG00000136352	P43699	Homeobox protein Nkx-2.1	clinvar
TTF1	HGNC:12397	ENSG00000125482	Q15361	Transcription termination factor 1	clinvar
PAX8-AS1	HGNC:49271	ENSG00000189223		PAX8 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PAX8	Paired box protein Pax-8	Transcription factor for the thyroid-specific expression of the genes exclusively expressed in the thyroid cell type, maintaining the functional differentiation of such cells.
NKX2-1	Homeobox protein Nkx-2.1	Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor.
TTF1	Transcription termination factor 1	Multifunctional nucleolar protein that terminates ribosomal gene transcription, mediates replication fork arrest and regulates RNA polymerase I transcription on chromatin.

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)
PAX8	Transcription factor	no		Paired_dom, Homeodomain-like_sf, Pax2_C
NKX2-1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
TTF1	Other/Unknown	no		SANT/Myb, TTF1-like
PAX8-AS1	Other/Unknown	no

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
left lobe of thyroid gland	3
right lobe of thyroid gland	3
thyroid gland	2
buccal mucosa cell	1
oocyte	1
trabecular bone tissue	1
metanephros cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PAX8	242	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
NKX2-1	101	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
TTF1	287	ubiquitous	marker	buccal mucosa cell, trabecular bone tissue, oocyte
PAX8-AS1	212	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NKX2-1	2,403
PAX8	1,994
TTF1	1,052
PAX8-AS1	0

Intra-cohort edges

A	B	Sources
NKX2-1	PAX8	biogrid_interaction, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NKX2-1	P43699	2
PAX8	Q06710	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TTF1	Q15361	57.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 4 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of intermediate mesoderm	1	713.8×	0.010	PAX8
Formation of the nephric duct	1	317.2×	0.011	PAX8
Surfactant metabolism	1	184.2×	0.011	TTF1
RNA Polymerase I Transcription Termination	1	163.1×	0.011	TTF1
RNA Polymerase I Transcription Initiation	1	112.0×	0.012	TTF1
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	1	76.1×	0.015	TTF1
NoRC negatively regulates rRNA expression	1	52.4×	0.019	TTF1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
thyroid gland development	2	362.4×	8e-04	PAX8, NKX2-1
regulation of thyroid-stimulating hormone secretion	1	5617.3×	0.003	PAX8
developmental induction	1	2808.7×	0.003	NKX2-1
pronephric field specification	1	2808.7×	0.003	PAX8
metanephric comma-shaped body morphogenesis	1	2808.7×	0.003	PAX8
obsolete negative regulation of mesenchymal cell apoptotic process involved in metanephric nephron morphogenesis	1	2808.7×	0.003	PAX8
obsolete negative regulation of apoptotic process involved in metanephric collecting duct development	1	2808.7×	0.003	PAX8
obsolete negative regulation of apoptotic process involved in metanephric nephron tubule development	1	2808.7×	0.003	PAX8
positive regulation of metanephric DCT cell differentiation	1	2808.7×	0.003	PAX8
termination of RNA polymerase I transcription	1	1872.4×	0.003	TTF1
cerebral cortex GABAergic interneuron differentiation	1	1872.4×	0.003	NKX2-1
negative regulation of mesenchymal cell apoptotic process involved in metanephros development	1	1872.4×	0.003	PAX8
metanephric distal convoluted tubule development	1	1404.3×	0.003	PAX8
metanephric S-shaped body morphogenesis	1	1404.3×	0.003	PAX8
positive regulation of thyroid hormone generation	1	1404.3×	0.003	PAX8
globus pallidus development	1	1123.5×	0.003	NKX2-1
forebrain neuron fate commitment	1	1123.5×	0.003	NKX2-1
club cell differentiation	1	1123.5×	0.003	NKX2-1
metanephric epithelium development	1	1123.5×	0.003	PAX8
metanephric nephron tubule formation	1	1123.5×	0.003	PAX8
regulation of metanephric nephron tubule epithelial cell differentiation	1	1123.5×	0.003	PAX8
cellular response to gonadotropin stimulus	1	936.2×	0.003	PAX8
otic vesicle development	1	936.2×	0.003	PAX8
positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis	1	936.2×	0.003	PAX8
pronephros development	1	802.5×	0.004	PAX8
mesenchymal to epithelial transition involved in metanephros morphogenesis	1	702.2×	0.004	PAX8
forebrain dorsal/ventral pattern formation	1	702.2×	0.004	NKX2-1
lung saccule development	1	702.2×	0.004	NKX2-1
type II pneumocyte differentiation	1	702.2×	0.004	NKX2-1
transcription initiation at RNA polymerase I promoter	1	624.1×	0.004	TTF1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PAX8	SORAFENIB TOSYLATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PAX8	14	4
NKX2-1	0	0
TTF1	0	0
PAX8-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SORAFENIB TOSYLATE	4	PAX8
MITOXANTRONE HYDROCHLORIDE	4	PAX8
TEGASEROD MALEATE	4	PAX8
DAUNORUBICIN HYDROCHLORIDE	4	PAX8
DIGOXIN	4	PAX8
DOXORUBICIN HYDROCHLORIDE	4	PAX8
HEXACHLOROPHENE	4	PAX8
THIOGUANINE	4	PAX8
CHLORHEXIDINE	4	PAX8
VORINOSTAT	4	PAX8
ENPIROLINE	2	PAX8
PINAFIDE	2	PAX8
LANATOSIDE C	2	PAX8
IODOQUINOL	2	PAX8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PAX8	3	Functional:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

14 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)
SORAFENIB TOSYLATE	4	PAX8
MITOXANTRONE HYDROCHLORIDE	4	PAX8
TEGASEROD MALEATE	4	PAX8
DAUNORUBICIN HYDROCHLORIDE	4	PAX8
DIGOXIN	4	PAX8
DOXORUBICIN HYDROCHLORIDE	4	PAX8
HEXACHLOROPHENE	4	PAX8
THIOGUANINE	4	PAX8
CHLORHEXIDINE	4	PAX8
VORINOSTAT	4	PAX8
ENPIROLINE	2	PAX8
PINAFIDE	2	PAX8
LANATOSIDE C	2	PAX8
IODOQUINOL	2	PAX8

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PAX8
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	3	NKX2-1, TTF1, PAX8-AS1

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)
NKX2-1	0	PAX8
TTF1	0	—
PAX8-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.