Hypothyroidism, congenital, nongoitrous, 9

Summary

Hypothyroidism, congenital, nongoitrous, 9 (MONDO:0026732) is a disease caused by IRS4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: IRS4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypothyroidism, congenital, nongoitrous, 9
Mondo ID	MONDO:0026732
OMIM	301035
DOID	DOID:0111835
UMLS	C5231396
MedGen	1684807
GARD	0025487
Is cancer (heuristic)	no

Also known as: CHNG9 · hypothyroidism, congenital, nongoitrous, 9, X-linked recessive

Data availability: 8 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, 9

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, 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

8 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 benign, 1 likely pathogenic, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
691493	NM_001379150.1(IRS4):c.1772dup (p.Lys592fs)	IRS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
691494	NM_001379150.1(IRS4):c.3161_3165del (p.Cys1054fs)	IRS4	Pathogenic	no assertion criteria provided
691492	NM_001379150.1(IRS4):c.643G>T (p.Gly215Ter)	IRS4	Likely pathogenic	criteria provided, single submitter
1029727	NM_001379150.1(IRS4):c.3215C>T (p.Ala1072Val)	IRS4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3110933	NM_001379150.1(IRS4):c.1766G>A (p.Gly589Glu)	IRS4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891407	NM_001379150.1(IRS4):c.2156C>T (p.Pro719Leu)	IRS4	Uncertain significance	criteria provided, single submitter
1284731	NM_001379150.1(IRS4):c.2635C>G (p.His879Asp)	IRS4	Benign	criteria provided, multiple submitters, no conflicts
1300045	NM_001379150.1(IRS4):c.63G>A (p.Ala21=)	IRS4	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
IRS4	Strong	X-linked	hypothyroidism, congenital, nongoitrous, 9	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
IRS4	HGNC:6128	ENSG00000133124	O14654	Insulin receptor substrate 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IRS4	Insulin receptor substrate 4	Acts as an interface between multiple growth factor receptors possessing tyrosine kinase activity, such as insulin receptor, IGF1R and FGFR1, and a complex network of intracellular signaling molecules containing SH2 domains.

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)
IRS4	Scaffold/PPI	no		PH_domain, IRS_PTB, PH-like_dom_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
adenohypophysis	1
ovary	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IRS4	38	broad	marker	pituitary gland, adenohypophysis, ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IRS4	2,198

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IRS4	O14654	49.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
IGF1R signaling cascade	1	1427.5×	0.002	IRS4
IRS-related events triggered by IGF1R	1	1038.2×	0.002	IRS4
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	1	951.7×	0.002	IRS4
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.024	IRS4
Signal Transduction	1	10.2×	0.098	IRS4

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
insulin receptor signaling pathway	1	221.7×	0.009	IRS4
signal transduction	1	16.1×	0.062	IRS4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IRS4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	IRS4

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)
IRS4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.