hypothyroidism due to TSH receptor mutations

disease

On this page

Also known as CHNG1hypothyroidism, congenital, nongoitrous, 1hypothyroidism, congenital, nongoitrous, type 1TSH resistance

Summary

hypothyroidism due to TSH receptor mutations (MONDO:0010142) is a disease caused by TSHR (GenCC Definitive), with 5 cohort genes and 1 clinical trial.

At a glance

Prevalence: Unknown (Worldwide)
Causal gene: TSHR (GenCC Definitive)
Cohort genes: 5
ClinVar variants: 150
Phenotypes (HPO): 28
Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0011789	Impaired sensitivity to thyroid stimulating hormone	Obligate (100%)
HP:0000851	Congenital hypothyroidism	Very frequent (80-99%)
HP:0002925	Elevated circulating thyroid-stimulating hormone concentration	Very frequent (80-99%)
HP:0006579	Prolonged neonatal jaundice	Frequent (30-79%)
HP:0025484	Increased circulating thyroglobulin concentration	Frequent (30-79%)
HP:0031219	Reduced radioactive iodine uptake	Frequent (30-79%)
HP:0031507	Decreased circulating thyroxine level	Frequent (30-79%)
HP:0000158	Macroglossia	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001537	Umbilical hernia	Occasional (5-29%)
HP:0001662	Bradycardia	Occasional (5-29%)
HP:0002019	Constipation	Occasional (5-29%)
HP:0003265	Neonatal hyperbilirubinemia	Occasional (5-29%)
HP:0004491	Large posterior fontanelle	Occasional (5-29%)
HP:0005930	Abnormality of epiphysis morphology	Occasional (5-29%)
HP:0005990	Thyroid hypoplasia	Occasional (5-29%)
HP:0008223	Compensated hypothyroidism	Occasional (5-29%)
HP:0008828	Delayed proximal femoral epiphyseal ossification	Occasional (5-29%)
HP:0008872	Feeding difficulties in infancy	Occasional (5-29%)
HP:0025429	Abnormal cry	Occasional (5-29%)
HP:0031220	Increased radioactive iodine uptake	Occasional (5-29%)
HP:0000853	Goiter	Excluded (0%)
HP:0011437	Maternal autoimmune disease	Excluded (0%)
HP:0030057	Autoimmune antibody positivity	Excluded (0%)
HP:0000969	Edema	Very rare (<1-4%)
HP:0001252	Hypotonia	Very rare (<1-4%)
HP:0002045	Hypothermia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypothyroidism due to TSH receptor mutations
Mondo ID	MONDO:0010142
OMIM	275200
Orphanet	90673
DOID	DOID:0070126
UMLS	C3493776
MedGen	487729
GARD	0016793
Is cancer (heuristic)	no

Also known as: CHNG1 · hypothyroidism, congenital, nongoitrous, 1 · hypothyroidism, congenital, nongoitrous, type 1 · TSH resistance

Data availability: 150 ClinVar variants · 4 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 due to TSH receptor mutations

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

150 retrieved; paginated sample, class counts are floors:

44 conflicting classifications of pathogenicity, 38 uncertain significance, 19 likely pathogenic, 13 pathogenic, 12 pathogenic/likely pathogenic, 12 benign, 11 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1204435	NM_000369.5(TSHR):c.1963_1964del (p.Thr655fs)	TSHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2664771	NM_000369.5(TSHR):c.1839C>A (p.Tyr613Ter)	TSHR	Pathogenic	criteria provided, single submitter
2736136	NM_000369.5(TSHR):c.1555C>T (p.Arg519Cys)	TSHR	Pathogenic	criteria provided, multiple submitters, no conflicts
2736138	NM_000369.5(TSHR):c.1957C>G (p.Leu653Val)	TSHR	Pathogenic	criteria provided, multiple submitters, no conflicts
3004919	NM_000369.5(TSHR):c.881+1G>T	TSHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3016055	NM_000369.5(TSHR):c.801_810del (p.Leu267fs)	TSHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3233814	NM_000369.5(TSHR):c.1348del (p.Arg450fs)	TSHR	Pathogenic	criteria provided, single submitter
3377496	NM_000369.5(TSHR):c.1552G>T (p.Glu518Ter)	TSHR	Pathogenic	criteria provided, single submitter
6434	NM_000369.5(TSHR):c.500T>A (p.Ile167Asn)	TSHR	Pathogenic	no assertion criteria provided
6435	NM_000369.5(TSHR):c.484C>G (p.Pro162Ala)	TSHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6439	NM_000369.5(TSHR):c.1637G>A (p.Trp546Ter)	TSHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6440	NM_000369.5(TSHR):c.970C>T (p.Gln324Ter)	TSHR	Pathogenic	no assertion criteria provided
6445	NM_000369.5(TSHR):c.1657G>A (p.Ala553Thr)	TSHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6458	NM_000369.5(TSHR):c.1798T>C (p.Cys600Arg)	TSHR	Pathogenic	no assertion criteria provided
6459	NM_000369.5(TSHR):c.1400T>C (p.Leu467Pro)	TSHR	Pathogenic	no assertion criteria provided
886255	NM_000369.5(TSHR):c.1556G>A (p.Arg519His)	TSHR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
917858	NM_000369.5(TSHR):c.545+5G>T	TSHR	Pathogenic	no assertion criteria provided
225505	NM_000369.5(TSHR):c.1349G>A (p.Arg450His)	TSHR-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3576836	NM_000369.5(TSHR):c.1465C>T (p.Gln489Ter)	TSHR-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3778827	NM_000369.5(TSHR):c.1426_1432del (p.Tyr476fs)	TSHR-AS1	Pathogenic	criteria provided, single submitter
426336	NM_000369.5(TSHR):c.418del (p.Met140fs)	TSHR-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6438	NM_000369.5(TSHR):c.326G>A (p.Arg109Gln)	TSHR-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6443	NM_000369.5(TSHR):c.1575C>A (p.Phe525Leu)	TSHR-AS1	Pathogenic	no assertion criteria provided
6444	NM_000369.5(TSHR):c.1170T>G (p.Cys390Trp)	TSHR-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6447	NM_000369.5(TSHR):c.1217_1234delinsCACG (p.Asn406fs)	TSHR-AS1	Pathogenic	no assertion criteria provided
4086209	NM_000369.5(TSHR):c.96del (p.Gln33fs)	CEP128	Likely pathogenic	criteria provided, single submitter
1050267	NM_000369.5(TSHR):c.1462T>C (p.Trp488Arg)	TSHR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
189249	NM_000369.5(TSHR):c.545+2_545+3del	TSHR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572312	NM_000369.5(TSHR):c.1207G>A (p.Asp403Asn)	TSHR	Likely pathogenic	criteria provided, single submitter
2682178	NM_000369.5(TSHR):c.1582C>T (p.Arg528Cys)	TSHR	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 7 · 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
TSHR	Definitive	Autosomal recessive	hypothyroidism due to TSH receptor mutations	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
TPO	Orphanet:95716	Familial thyroid dyshormonogenesis
IGSF1	Orphanet:329235	X-linked central congenital hypothyroidism with late-onset testicular enlargement

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TSHR	HGNC:12373	ENSG00000165409	P16473	Thyrotropin receptor	gencc,clinvar
TPO	HGNC:12015	ENSG00000115705	P07202	Thyroid peroxidase	clinvar
CEP128	HGNC:20359	ENSG00000100629	Q6ZU80	Centrosomal protein 128	clinvar
TSHR-AS1	HGNC:58172	ENSG00000284959		TSHR antisense RNA 1	clinvar
IGSF1	HGNC:5948	ENSG00000147255	Q8N6C5	Immunoglobulin superfamily member 1	clinvar

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.
TPO	Thyroid peroxidase	Iodination and coupling of the hormonogenic tyrosines in thyroglobulin to yield the thyroid hormones T(3) and T(4).
CEP128	Centrosomal protein 128	Is involved in the negative regulation of ciliogenesis and plays a role in spermatogenesis.
IGSF1	Immunoglobulin superfamily member 1	Seems to be a coreceptor in inhibin signaling, but seems not to be a high-affinity inhibin receptor.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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
Complement	1	53.6×	0.074
Antibody/Immunoglobulin	1	5.8×	0.256
GPCR	1	4.8×	0.256
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TSHR	GPCR	yes		GPCR_Rhodpsn, Gphrmn_rcpt_fam, TSH_rcpt
TPO	Complement	yes	1.11.1.8	EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, EGF
CEP128	Other/Unknown	no		CEP128
TSHR-AS1	Other/Unknown	no
IGSF1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of thyroid gland	3
thyroid gland	3
left lobe of thyroid gland	2
male germ line stem cell (sensu Vertebrata) in testis	2
bone marrow cell	1
thymus	1
adenohypophysis	1
pituitary gland	1
right atrium auricular region	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
TPO	132	tissue_specific	marker	left lobe of thyroid gland, thyroid gland, right lobe of thyroid gland
CEP128	186	ubiquitous	marker	bone marrow cell, thymus, male germ line stem cell (sensu Vertebrata) in testis
TSHR-AS1	134		marker	male germ line stem cell (sensu Vertebrata) in testis, right lobe of thyroid gland, thyroid gland
IGSF1	194	broad	marker	pituitary gland, adenohypophysis, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TSHR	1,672
CEP128	1,328
TPO	1,074
IGSF1	748
TSHR-AS1	0

Intra-cohort edges

A	B	Sources
TPO	TSHR	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TSHR	P16473	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TPO	P07202	84.00
CEP128	Q6ZU80	74.92
IGSF1	Q8N6C5	73.64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 5 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
Hormone ligand-binding receptors	1	475.8×	0.004	TSHR
Thyroxine biosynthesis	1	407.9×	0.004	TPO
G alpha (s) signalling events	1	36.6×	0.027	TSHR

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
thyroid-stimulating hormone signaling pathway	1	4213.0×	0.003	TSHR
cellular response to thyrotropin-releasing hormone	1	4213.0×	0.003	TSHR
cellular response to glycoprotein	1	1404.3×	0.005	TSHR
negative regulation of activin receptor signaling pathway	1	351.1×	0.013	IGSF1
hormone biosynthetic process	1	351.1×	0.013	TPO
thyroid hormone generation	1	247.8×	0.013	TPO
embryonic hemopoiesis	1	247.8×	0.013	TPO
hydrogen peroxide catabolic process	1	168.5×	0.015	TPO
sperm flagellum assembly	1	168.5×	0.015	CEP128
motile cilium assembly	1	145.3×	0.016	CEP128
immune response-regulating signaling pathway	1	113.9×	0.018	IGSF1
hormone-mediated signaling pathway	1	100.3×	0.019	TSHR
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger	1	78.0×	0.023	TSHR
positive regulation of cold-induced thermogenesis	1	40.9×	0.040	TSHR
response to oxidative stress	1	32.7×	0.046	TPO
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	28.3×	0.050	TSHR
intracellular protein localization	1	26.2×	0.051	CEP128
regulation of gene expression	1	20.9×	0.060	CEP128
cell-cell signaling	1	17.4×	0.068	TSHR
cell surface receptor signaling pathway	1	16.0×	0.070	TSHR
G protein-coupled receptor signaling pathway	1	9.1×	0.116	TSHR
positive regulation of cell population proliferation	1	8.4×	0.119	TSHR
regulation of DNA-templated transcription	1	7.9×	0.121	IGSF1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
TPO	PROPYLTHIOURACIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TSHR	354	4
TPO	3	4
CEP128	0	0
TSHR-AS1	0	0
IGSF1	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): 1.

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

Symbol	Assays	Type breakdown
TSHR	33	Functional:24, Binding:9
TPO	12	Binding:12

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TPO	1.11.1.8, 3.6.1.52	iodide peroxidase, diphosphoinositol-polyphosphate diphosphatase

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, TPO
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	IGSF1
E	Difficult family or no structure, no drug	2	CEP128, TSHR-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)
CEP128	0	—
TSHR-AS1	0	—
IGSF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns

Cohort genes: TSHR, TPO, CEP128, TSHR-AS1, IGSF1