Hypothyroidism, congenital, nongoitrous, 7

Summary

Hypothyroidism, congenital, nongoitrous, 7 (MONDO:0032819) is a disease caused by TRHR (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TRHR (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 7
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0008245	Pituitary hypothyroidism	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0025483	Abnormal circulating thyroglobulin concentration	Frequent (30-79%)
HP:0025502	Overweight	Frequent (30-79%)
HP:0031219	Reduced radioactive iodine uptake	Frequent (30-79%)
HP:0031507	Decreased circulating thyroxine level	Frequent (30-79%)
HP:0032210	Decreased circulating free T3	Frequent (30-79%)
HP:0000707	Abnormality of the nervous system	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000870	Increased circulating prolactin concentration	Frequent (30-79%)
HP:0000958	Dry skin	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001609	Hoarse voice	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0005990	Thyroid hypoplasia	Frequent (30-79%)
HP:0006579	Prolonged neonatal jaundice	Frequent (30-79%)
HP:0008202	Reduced circulating prolactin concentration	Frequent (30-79%)
HP:0000853	Goiter	Excluded (0%)
HP:0002925	Elevated circulating thyroid-stimulating hormone concentration	Excluded (0%)
HP:0011437	Maternal autoimmune disease	Excluded (0%)
HP:0030057	Autoimmune antibody positivity	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypothyroidism, congenital, nongoitrous, 7
Mondo ID	MONDO:0032819
OMIM	618573
Orphanet	99832
DOID	DOID:0111836
SNOMED CT	725462002
UMLS	C1861106
MedGen	349957
GARD	0016914
Is cancer (heuristic)	no

Also known as: central hypothyroidism due to TRH receptor deficiency · CHNG7 · hypothyroidism, congenital, nongoitrous, 7 · resistance to thyrotropin-releasing hormone syndrome · thyrotropin-releasing hormone resistance, generalised · TRH resistance syndrome

Data availability: 7 ClinVar variants · 2 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, 7

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, 2, hypothyroidism, congenital, nongoitrous, 8, hypothyroidism, congenital, nongoitrous, 9

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

7 retrieved; paginated sample, class counts are floors:

4 likely pathogenic, 2 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
12682	NM_003301.7(TRHR):c.49C>T (p.Arg17Ter)	TRHR	Pathogenic	criteria provided, single submitter
689396	NM_003301.7(TRHR):c.392T>C (p.Ile131Thr)	TRHR	Pathogenic	no assertion criteria provided
12681	NM_003301.7(TRHR):c.343_352delinsA (p.Ser115_Ala118delinsThr)	TRHR	Likely pathogenic	criteria provided, single submitter
3595038	NM_003301.7(TRHR):c.597_598del (p.Phe199fs)	TRHR	Likely pathogenic	criteria provided, single submitter
4849395	NM_003301.7(TRHR):c.1016del (p.Gln339fs)	TRHR	Likely pathogenic	criteria provided, single submitter
689395	NM_003301.7(TRHR):c.242C>G (p.Pro81Arg)	TRHR	Likely pathogenic	criteria provided, single submitter
4080586	NM_003301.7(TRHR):c.110G>T (p.Gly37Val)	TRHR	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
TRHR	Strong	Autosomal recessive	hypothyroidism, congenital, nongoitrous, 7	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRHR	Orphanet:99832	Resistance to thyrotropin-releasing hormone syndrome

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
TRHR	HGNC:12299	ENSG00000174417	P34981	Thyrotropin-releasing hormone receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRHR	Thyrotropin-releasing hormone receptor	Receptor for thyrotropin-releasing hormone (TRH).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRHR	GPCR	yes		GPCR_Rhodpsn, TRH_rcpt_1, GPCR_Rhodpsn_7TM

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
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
metanephric glomerulus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRHR	22		yes	male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon, metanephric glomerulus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRHR	1,078

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRHR	P34981	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Peptide ligand-binding receptors	1	74.2×	0.017	TRHR
G alpha (q) signalling events	1	57.4×	0.017	TRHR

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
phospholipase C-activating G protein-coupled receptor signaling pathway	1	131.7×	0.015	TRHR
G protein-coupled receptor signaling pathway	1	36.2×	0.028	TRHR

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
TRHR	PROTIRELIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRHR	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PROTIRELIN	4	TRHR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TRHR	15	Binding:12, Functional:3

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

1 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)
PROTIRELIN	4	TRHR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TRHR
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.