Hypothyroidism, congenital, nongoitrous, 8

Summary

Hypothyroidism, congenital, nongoitrous, 8 (MONDO:0026731) is a disease caused by TBL1X (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TBL1X (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypothyroidism, congenital, nongoitrous, 8
Mondo ID	MONDO:0026731
OMIM	301033
DOID	DOID:0111837
UMLS	C5231395
MedGen	1684717
GARD	0025486
Is cancer (heuristic)	no

Also known as: CHNG8

Data availability: 12 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, 8

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, 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

12 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
691491	NM_005647.4(TBL1X):c.1015C>T (p.Arg339Ter)	TBL1X	Likely pathogenic	criteria provided, single submitter
2636524	NM_005647.4(TBL1X):c.1648T>C (p.Phe550Leu)	TBL1X	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1803274	NM_005647.4(TBL1X):c.1369A>T (p.Ile457Phe)	TBL1X	Uncertain significance	criteria provided, single submitter
691488	NM_005647.4(TBL1X):c.1246A>T (p.Asn416Tyr)	TBL1X	Uncertain significance	criteria provided, single submitter
691489	NM_005647.4(TBL1X):c.1510C>T (p.His504Tyr)	TBL1X	Uncertain significance	criteria provided, single submitter
691490	NM_005647.4(TBL1X):c.1526A>G (p.Tyr509Cys)	TBL1X	Uncertain significance	criteria provided, single submitter
870340	NM_005647.4(TBL1X):c.1249G>A (p.Ala417Thr)	TBL1X	Uncertain significance	criteria provided, single submitter
870341	NM_005647.4(TBL1X):c.1258T>C (p.Trp420Arg)	TBL1X	Uncertain significance	criteria provided, single submitter
1233016	NM_005647.4(TBL1X):c.749+15G>A	TBL1X	Benign	criteria provided, multiple submitters, no conflicts
1334929	NM_005647.4(TBL1X):c.749+22dup	TBL1X	Benign	criteria provided, single submitter
1334930	NM_005647.4(TBL1X):c.892-24G>T	TBL1X	Benign	criteria provided, multiple submitters, no conflicts
1334931	NM_005647.4(TBL1X):c.1054-41C>A	TBL1X	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
TBL1X	Strong	X-linked	hypothyroidism, congenital, nongoitrous, 8	3

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
TBL1X	HGNC:11585	ENSG00000101849	O60907	F-box-like/WD repeat-containing protein TBL1X	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBL1X	F-box-like/WD repeat-containing protein TBL1X	F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBL1X	Scaffold/PPI	no		WD40_rpt, LisH, Quinoprotein_ADH-like_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cauda epididymis	1
corpus epididymis	1
seminal vesicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBL1X	280	ubiquitous	marker	cauda epididymis, seminal vesicle, corpus epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBL1X	6,393

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TBL1X	O60907	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 61. 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
Loss of MECP2 binding ability to the NCoR/SMRT complex	1	1631.4×	0.009	TBL1X
Loss of function of MECP2 in Rett syndrome	1	1427.5×	0.009	TBL1X
Pervasive developmental disorders	1	1427.5×	0.009	TBL1X
Disorders of Developmental Biology	1	1427.5×	0.009	TBL1X
Disorders of Nervous System Development	1	1427.5×	0.009	TBL1X
R-HSA-1368082	1	713.8×	0.010	TBL1X
BMAL1:CLOCK,NPAS2 activates circadian expression	1	423.0×	0.010	TBL1X
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	407.9×	0.010	TBL1X
Signaling by NOTCH1 in Cancer	1	407.9×	0.010	TBL1X
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	407.9×	0.010	TBL1X
Notch-HLH transcription pathway	1	407.9×	0.010	TBL1X
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	1	407.9×	0.010	TBL1X
NR1H2 and NR1H3-mediated signaling	1	393.8×	0.010	TBL1X
Regulation of MECP2 expression and activity	1	368.4×	0.010	TBL1X
Signaling by NOTCH1	1	356.9×	0.010	TBL1X
R-HSA-400253	1	346.1×	0.010	TBL1X
HCMV Infection	1	326.3×	0.010	TBL1X
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	317.2×	0.010	TBL1X
Transcriptional Regulation by MECP2	1	317.2×	0.010	TBL1X
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	308.6×	0.010	TBL1X
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	292.8×	0.010	TBL1X
Activation of gene expression by SREBF (SREBP)	1	259.6×	0.011	TBL1X
NOTCH1 Intracellular Domain Regulates Transcription	1	237.9×	0.011	TBL1X
Heme signaling	1	215.5×	0.011	TBL1X
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	215.5×	0.011	TBL1X
Transcriptional activation of mitochondrial biogenesis	1	203.9×	0.011	TBL1X
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.011	TBL1X
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.011	TBL1X
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	196.9×	0.011	TBL1X
Cytoprotection by HMOX1	1	184.2×	0.011	TBL1X

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
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.043	TBL1X
sensory perception of sound	1	100.9×	0.043	TBL1X
protein stabilization	1	66.9×	0.043	TBL1X
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.043	TBL1X
proteolysis	1	34.2×	0.053	TBL1X
positive regulation of DNA-templated transcription	1	27.9×	0.054	TBL1X
negative regulation of transcription by RNA polymerase II	1	17.7×	0.073	TBL1X
positive regulation of transcription by RNA polymerase II	1	14.9×	0.076	TBL1X
regulation of transcription by RNA polymerase II	1	11.7×	0.086	TBL1X

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TBL1X	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TBL1X	9	Binding:9

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	1	TBL1X

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)
TBL1X	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.