Congenital nongoitrous hypothyroidism 6

Summary

Congenital nongoitrous hypothyroidism 6 (MONDO:0013757) is a disease caused by THRA (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: THRA (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital nongoitrous hypothyroidism 6
Mondo ID	MONDO:0013757
OMIM	614450
DOID	DOID:0070128
UMLS	C3280817
MedGen	482447
GARD	0024946
Is cancer (heuristic)	no

Also known as: CHNG6 · hypothyroidism, congenital, nongoitrous caused by mutation in THRA · hypothyroidism, congenital, nongoitrous, 6 · hypothyroidism, congenital, nongoitrous, type 6 · THRA hypothyroidism, congenital, nongoitrous

Data availability: 18 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 › congenital nongoitrous hypothyroidism 6

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

18 retrieved; paginated sample, class counts are floors:

6 pathogenic, 6 uncertain significance, 4 likely pathogenic, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1299533	NM_003250.6(THRA):c.1416dup (p.Ser473fs)	NR1D1	Pathogenic	criteria provided, single submitter
192271	NM_199334.5(THRA):c.1176C>A (p.Cys392Ter)	THRA	Pathogenic	no assertion criteria provided
192272	NM_199334.5(THRA):c.1207G>A (p.Glu403Lys)	THRA	Pathogenic	criteria provided, multiple submitters, no conflicts
192273	NM_199334.5(THRA):c.1193C>G (p.Pro398Arg)	THRA	Pathogenic	no assertion criteria provided
29913	NM_199334.5(THRA):c.134G>T (p.Ser45Ile)	THRA	Pathogenic	no assertion criteria provided
29914	NM_199334.5(THRA):c.1110G>C (p.Lys370Asn)	THRA	Pathogenic	no assertion criteria provided
522121	NM_199334.5(THRA):c.788C>T (p.Ala263Val)	THRA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679212	NM_199334.5(THRA):c.818C>A (p.Thr273Asn)	THRA	Likely pathogenic	criteria provided, single submitter
3024267	NM_199334.5(THRA):c.896T>C (p.Ile299Thr)	THRA	Likely pathogenic	criteria provided, single submitter
3254965	NM_199334.5(THRA):c.1141C>T (p.His381Tyr)	THRA	Likely pathogenic	criteria provided, single submitter
992628	NM_199334.5(THRA):c.518A>G (p.Glu173Gly)	THRA	Likely pathogenic	criteria provided, single submitter
561132	NM_199334.5(THRA):c.54-1G>A	THRA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1319909	NM_001190919.2(THRA):c.1130C>T (p.Ser377Leu)	NR1D1	Uncertain significance	no assertion criteria provided
225490	NM_001190918.2(THRA):c.1249C>T (p.Arg417Ter)	NR1D1	Uncertain significance	criteria provided, single submitter
1709428	NM_199334.5(THRA):c.121+1G>A	THRA	Uncertain significance	criteria provided, single submitter
4293451	NM_199334.5(THRA):c.614C>T (p.Pro205Leu)	THRA	Uncertain significance	criteria provided, single submitter
4531650	NM_199334.5(THRA):c.850C>T (p.Arg284Trp)	THRA	Uncertain significance	criteria provided, single submitter
803389	NM_199334.5(THRA):c.425G>T (p.Arg142Leu)	THRA	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
THRA	Definitive	Autosomal dominant	congenital nongoitrous hypothyroidism 6	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
THRA	Orphanet:566231	Resistance to thyroid hormone due to a mutation in thyroid hormone receptor alpha

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
THRA	HGNC:11796	ENSG00000126351	P10827	Thyroid hormone receptor alpha	gencc,clinvar
NR1D1	HGNC:7962	ENSG00000126368	P20393	Nuclear receptor subfamily 1 group D member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
THRA	Thyroid hormone receptor alpha	Nuclear hormone receptor that can act as a repressor or activator of transcription.
NR1D1	Nuclear receptor subfamily 1 group D member 1	Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner.

Protein-family classification

Druggable: 2 · 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
Nuclear receptor	2	385.9×	7e-06

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
THRA	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
NR1D1	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
middle frontal gyrus	1
nucleus accumbens	1
pancreatic ductal cell	1
skin of abdomen	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
THRA	290	ubiquitous	marker	nucleus accumbens, cortical plate, middle frontal gyrus
NR1D1	289	ubiquitous	marker	skin of leg, skin of abdomen, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
THRA	2,052
NR1D1	1,519

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
THRA	P10827	10
NR1D1	P20393	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 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
Nuclear Receptor transcription pathway	2	200.3×	3e-04	THRA, NR1D1
Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters	1	439.2×	0.012	NR1D1
The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex	1	356.9×	0.012	NR1D1
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	1	237.9×	0.013	NR1D1
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	1	203.9×	0.013	NR1D1
SUMOylation of intracellular receptors	1	167.9×	0.013	THRA
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	146.4×	0.013	NR1D1
Heme signaling	1	107.7×	0.014	NR1D1
Transcriptional activation of mitochondrial biogenesis	1	102.0×	0.014	NR1D1
PPARA activates gene expression	1	47.2×	0.027	NR1D1
RNA Polymerase II Transcription	1	11.3×	0.103	THRA
Gene expression (Transcription)	1	8.9×	0.118	THRA
Generic Transcription Pathway	1	7.5×	0.128	THRA

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
hormone-mediated signaling pathway	2	401.2×	3e-04	THRA, NR1D1
regulation of myeloid cell apoptotic process	1	8426.0×	0.002	THRA
regulation of circadian sleep/wake cycle	1	8426.0×	0.002	NR1D1
negative regulation of RNA polymerase II transcription preinitiation complex assembly	1	4213.0×	0.002	THRA
negative regulation of DNA-templated transcription initiation	1	4213.0×	0.002	THRA
female courtship behavior	1	2808.7×	0.002	THRA
positive regulation of female receptivity	1	2808.7×	0.002	THRA
circadian temperature homeostasis	1	2808.7×	0.002	NR1D1
negative regulation of astrocyte activation	1	2808.7×	0.002	NR1D1
positive regulation of bile acid biosynthetic process	1	2808.7×	0.002	NR1D1
thyroid hormone receptor signaling pathway	1	2106.5×	0.002	THRA
positive regulation of thyroid hormone receptor signaling pathway	1	2106.5×	0.002	THRA
regulation of lipid catabolic process	1	2106.5×	0.002	THRA
response to leptin	1	1203.7×	0.003	NR1D1
regulation of type B pancreatic cell proliferation	1	1053.2×	0.003	NR1D1
negative regulation of microglial cell activation	1	1053.2×	0.003	NR1D1
negative regulation of DNA-templated transcription	2	31.6×	0.003	THRA, NR1D1
negative regulation of neuroinflammatory response	1	936.2×	0.003	NR1D1
cell differentiation	2	29.1×	0.003	THRA, NR1D1
type I pneumocyte differentiation	1	766.0×	0.003	THRA
regulation of fat cell differentiation	1	648.1×	0.004	NR1D1
negative regulation of toll-like receptor 4 signaling pathway	1	561.7×	0.004	NR1D1
intracellular receptor signaling pathway	1	495.6×	0.005	NR1D1
glycogen biosynthetic process	1	468.1×	0.005	NR1D1
regulation of insulin secretion involved in cellular response to glucose stimulus	1	468.1×	0.005	NR1D1
cartilage condensation	1	383.0×	0.005	THRA
proteasomal protein catabolic process	1	383.0×	0.005	NR1D1
retinoic acid receptor signaling pathway	1	324.1×	0.006	THRA
negative regulation of transcription by RNA polymerase II	2	17.7×	0.006	THRA, NR1D1
intracellular glucose homeostasis	1	290.6×	0.006	NR1D1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
THRA	LIOTHYRONINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
THRA	12	4
NR1D1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LIOTHYRONINE	4	THRA
LEVOTHYROXINE	4	THRA
ROXADUSTAT	4	THRA
RESMETIROM	4	THRA
AMIODARONE	4	THRA
EPROTIROME	3	THRA
TIRATRICOL	3	THRA
SOBETIROME	2	THRA
AXITIROME	2	THRA
THYROPROPIC ACID	2	THRA
MB07811	2	THRA
DETROTHYRONINE	2	THRA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
THRA	140	Binding:115, Functional:23, ADMET:2
NR1D1	32	Binding:22, Functional:10

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
THRA	140

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

12 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)
LIOTHYRONINE	4	THRA
LEVOTHYROXINE	4	THRA
ROXADUSTAT	4	THRA
RESMETIROM	4	THRA
AMIODARONE	4	THRA
EPROTIROME	3	THRA
TIRATRICOL	3	THRA
SOBETIROME	2	THRA
AXITIROME	2	THRA
THYROPROPIC ACID	2	THRA
MB07811	2	THRA
DETROTHYRONINE	2	THRA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	THRA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	NR1D1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
NR1D1	32	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.