Athyreosis

Summary

Athyreosis (MONDO:0019855) is a disease with 4 cohort genes.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 4
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3.5	Europe	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0000158	Macroglossia	Very frequent (80-99%)
HP:0000239	Large fontanelles	Very frequent (80-99%)
HP:0000271	Abnormality of the face	Very frequent (80-99%)
HP:0000280	Coarse facial features	Very frequent (80-99%)
HP:0000821	Hypothyroidism	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0002019	Constipation	Very frequent (80-99%)
HP:0003270	Abdominal distention	Very frequent (80-99%)
HP:0008191	Thyroid agenesis	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0025483	Abnormal circulating thyroglobulin concentration	Very frequent (80-99%)
HP:0100786	Hypersomnia	Very frequent (80-99%)
HP:0000282	Facial edema	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001537	Umbilical hernia	Frequent (30-79%)
HP:0001615	Hoarse cry	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0006579	Prolonged neonatal jaundice	Frequent (30-79%)
HP:0008282	Unconjugated hyperbilirubinemia	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0033850	Coldness	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	athyreosis
Mondo ID	MONDO:0019855
Orphanet	95713
UMLS	C0749420
MedGen	155447
GARD	0016842
Is cancer (heuristic)	no

Data availability: 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › thyroid gland disorder › inherited thyroid metabolism disease › thyroid hormone resistance syndrome › generalized resistance to thyroid hormone › athyreosis

Related subtypes (5): thyroid hormone resistance, generalized, autosomal dominant, thyroid hormone resistance, generalized, autosomal recessive, thyroid ectopia, thyroid hemiagenesis, thyroid hypoplasia

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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 44 · Orphanet: 24 · 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	Supportive	Autosomal dominant	athyreosis	17
PAX8	Supportive	Autosomal dominant	athyreosis	5
SLC26A4	Supportive	Autosomal dominant	athyreosis	10
TSHR	Supportive	Autosomal dominant	athyreosis	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TSHR	Orphanet:424	Familial hyperthyroidism due to mutations in TSH receptor
TSHR	Orphanet:90673	Hypothyroidism due to TSH receptor mutations
TSHR	Orphanet:95713	Athyreosis
TSHR	Orphanet:95720	Thyroid hypoplasia
TSHR	Orphanet:99819	Familial gestational hyperthyroidism
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
PAX8	Orphanet:146	Differentiated thyroid carcinoma
PAX8	Orphanet:95712	Thyroid ectopia
PAX8	Orphanet:95713	Athyreosis
PAX8	Orphanet:95720	Thyroid hypoplasia
SLC26A4	Orphanet:705	Pendred syndrome
SLC26A4	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
SLC26A4	Orphanet:95713	Athyreosis
SLC26A4	Orphanet:95720	Thyroid hypoplasia

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
TSHR	HGNC:12373	ENSG00000165409	P16473	Thyrotropin receptor	gencc
NKX2-5	HGNC:2488	ENSG00000183072	P52952	Homeobox protein Nkx-2.5	gencc
PAX8	HGNC:8622	ENSG00000125618	Q06710	Paired box protein Pax-8	gencc
SLC26A4	HGNC:8818	ENSG00000091137	O43511	Pendrin	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TSHR	Thyrotropin receptor	Receptor for the thyroid-stimulating hormone (TSH) or thyrotropin.
NKX2-5	Homeobox protein Nkx-2.5	Transcription factor required for the development of the heart and the spleen.
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.
SLC26A4	Pendrin	Sodium-independent transporter of chloride and iodide.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.5

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
Transporter	1	19.4×	0.112
Transcription factor	2	4.1×	0.112
GPCR	1	6.0×	0.157

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSHR	GPCR	yes		GPCR_Rhodpsn, Gphrmn_rcpt_fam, TSH_rcpt
NKX2-5	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
PAX8	Transcription factor	no		Paired_dom, Homeodomain-like_sf, Pax2_C
SLC26A4	Transporter	yes		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom

Expression context

Cohort genes with no expression data: 0.

3 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
right lobe of thyroid gland	3
thyroid gland	3
left lobe of thyroid gland	2
apex of heart	1
cardiac atrium	1
right atrium auricular region	1
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TSHR	169	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
NKX2-5	98	broad	yes	apex of heart, right atrium auricular region, cardiac atrium
PAX8	242	ubiquitous	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
SLC26A4	190	tissue_specific	marker	palpebral conjunctiva, right lobe of thyroid gland, thyroid gland

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NKX2-5	2,355
PAX8	1,994
TSHR	1,672
SLC26A4	1,648

Intra-cohort edges

A	B	Sources
PAX8	TSHR	string_interaction
SLC26A4	TSHR	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TSHR	P16473	9
NKX2-5	P52952	4
PAX8	Q06710	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC26A4	O43511	82.72

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. 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
Defective SLC26A4 causes Pendred syndrome (PDS)	1	2855.0×	0.005	SLC26A4
Formation of intermediate mesoderm	1	356.9×	0.013	PAX8
Inorganic anion exchange by SLC26 transporters	1	317.2×	0.013	SLC26A4
Hormone ligand-binding receptors	1	237.9×	0.013	TSHR
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	190.3×	0.013	NKX2-5
Physiological factors	1	167.9×	0.013	NKX2-5
Formation of the nephric duct	1	158.6×	0.013	PAX8
Cardiogenesis	1	105.7×	0.018	NKX2-5
SLC transporter disorders	1	51.0×	0.032	SLC26A4
Disorders of transmembrane transporters	1	34.8×	0.042	SLC26A4
R-HSA-425393	1	32.4×	0.042	SLC26A4
G alpha (s) signalling events	1	18.3×	0.067	TSHR
SLC-mediated transmembrane transport	1	14.8×	0.076	SLC26A4
Transport of small molecules	1	6.3×	0.161	SLC26A4
Disease	1	3.3×	0.273	SLC26A4

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 cardiac muscle cell apoptotic process	2	271.8×	0.001	NKX2-5, PAX8
thyroid gland development	2	271.8×	0.001	NKX2-5, PAX8
Purkinje myocyte differentiation	1	4213.0×	0.003	NKX2-5
septum secundum development	1	4213.0×	0.003	NKX2-5
thyroid-stimulating hormone signaling pathway	1	4213.0×	0.003	TSHR
cellular response to thyrotropin-releasing hormone	1	4213.0×	0.003	TSHR
regulation of thyroid-stimulating hormone secretion	1	4213.0×	0.003	PAX8
right ventricular cardiac muscle tissue morphogenesis	1	2106.5×	0.003	NKX2-5
pronephric field specification	1	2106.5×	0.003	PAX8
atrioventricular node cell fate commitment	1	2106.5×	0.003	NKX2-5
metanephric comma-shaped body morphogenesis	1	2106.5×	0.003	PAX8
obsolete negative regulation of mesenchymal cell apoptotic process involved in metanephric nephron morphogenesis	1	2106.5×	0.003	PAX8
obsolete negative regulation of apoptotic process involved in metanephric collecting duct development	1	2106.5×	0.003	PAX8
obsolete negative regulation of apoptotic process involved in metanephric nephron tubule development	1	2106.5×	0.003	PAX8
positive regulation of metanephric DCT cell differentiation	1	2106.5×	0.003	PAX8
cardiac ventricle formation	1	1404.3×	0.003	NKX2-5
apoptotic process involved in heart morphogenesis	1	1404.3×	0.003	NKX2-5
proepicardium development	1	1404.3×	0.003	NKX2-5
pulmonary myocardium development	1	1404.3×	0.003	NKX2-5
inorganic anion transport	1	1404.3×	0.003	SLC26A4
ventricular cardiac myofibril assembly	1	1404.3×	0.003	NKX2-5
atrial cardiac muscle cell development	1	1404.3×	0.003	NKX2-5
negative regulation of mesenchymal cell apoptotic process involved in metanephros development	1	1404.3×	0.003	PAX8
cellular response to glycoprotein	1	1404.3×	0.003	TSHR
bundle of His development	1	1053.2×	0.004	NKX2-5
atrial cardiac muscle tissue development	1	1053.2×	0.004	NKX2-5
positive regulation of cardioblast differentiation	1	1053.2×	0.004	NKX2-5
atrioventricular node cell development	1	1053.2×	0.004	NKX2-5
metanephric distal convoluted tubule development	1	1053.2×	0.004	PAX8
metanephric S-shaped body morphogenesis	1	1053.2×	0.004	PAX8

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
TSHR	LEVOSALBUTAMOL
PAX8	SORAFENIB TOSYLATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TSHR	354	4
PAX8	14	4
NKX2-5	0	0
SLC26A4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LEVOSALBUTAMOL	4	TSHR
PROGESTERONE	4	TSHR
DICLOFENAC SODIUM	4	TSHR
CLOTRIMAZOLE	4	TSHR
DAPSONE	4	TSHR
COLCHICINE	4	TSHR
OXAPROZIN	4	TSHR
BUMETANIDE	4	TSHR
GLIPIZIDE	4	TSHR
CARBAMAZEPINE	4	TSHR
METHYL SALICYLATE	4	TSHR
PHENELZINE	4	TSHR
EDROPHONIUM	4	TSHR
SULFAPHENAZOLE	4	TSHR
AMOXAPINE	4	TSHR
PYRIDOSTIGMINE	4	TSHR
ACETAMINOPHEN	4	TSHR
DICYCLOMINE	4	TSHR
IODIPAMIDE	4	TSHR
TESTOSTERONE PROPIONATE	4	TSHR
TETRABENAZINE	4	TSHR
CELECOXIB	4	TSHR
PROPANTHELINE	4	TSHR
BENOXINATE	4	TSHR
NICARDIPINE HYDROCHLORIDE	4	TSHR
PYRITHIONE ZINC	4	TSHR
GUANABENZ ACETATE	4	TSHR
PROPIOLACTONE	4	TSHR
CHLOROTRIANISENE	4	TSHR
PHENOXYBENZAMINE HYDROCHLORIDE	4	TSHR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC26A4	37	Binding:37
TSHR	33	Functional:24, Binding:9
PAX8	3	Functional:3

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

30 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)
LEVOSALBUTAMOL	4	TSHR
PROGESTERONE	4	TSHR
DICLOFENAC SODIUM	4	TSHR
CLOTRIMAZOLE	4	TSHR
DAPSONE	4	TSHR
COLCHICINE	4	TSHR
OXAPROZIN	4	TSHR
BUMETANIDE	4	TSHR
GLIPIZIDE	4	TSHR
CARBAMAZEPINE	4	TSHR
METHYL SALICYLATE	4	TSHR
PHENELZINE	4	TSHR
EDROPHONIUM	4	TSHR
SULFAPHENAZOLE	4	TSHR
AMOXAPINE	4	TSHR
PYRIDOSTIGMINE	4	TSHR
ACETAMINOPHEN	4	TSHR
DICYCLOMINE	4	TSHR
IODIPAMIDE	4	TSHR
TESTOSTERONE PROPIONATE	4	TSHR
TETRABENAZINE	4	TSHR
CELECOXIB	4	TSHR
PROPANTHELINE	4	TSHR
BENOXINATE	4	TSHR
NICARDIPINE HYDROCHLORIDE	4	TSHR
PYRITHIONE ZINC	4	TSHR
GUANABENZ ACETATE	4	TSHR
PROPIOLACTONE	4	TSHR
CHLOROTRIANISENE	4	TSHR
PHENOXYBENZAMINE HYDROCHLORIDE	4	TSHR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TSHR, PAX8
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	SLC26A4
E	Difficult family or no structure, no drug	1	NKX2-5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NKX2-5	0	—
SLC26A4	37	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.