intellectual disability, X-linked, with panhypopituitarism

Summary

intellectual disability, X-linked, with panhypopituitarism (MONDO:0010252) is a disease caused by SOX3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: SOX3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked, with panhypopituitarism
Mondo ID	MONDO:0010252
OMIM	300123
UMLS	C2678223
MedGen	394771
GARD	0024714
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked, with isolated growth hormone deficiency · intellectual disability, X-linked, with panhypopituitarism · mental retardation, X-linked, with isolated Growth hormone deficiency · mental retardation, X-linked, with panhypopituitarism

Data availability: 15 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › X-linked syndromic intellectual disability › X-linked intellectual disability with hypopituitarism › intellectual disability, X-linked, with panhypopituitarism

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

15 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 3 benign/likely benign, 3 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
444006	NM_005634.3(SOX3):c.449C>A (p.Ser150Tyr)	SOX3	Likely pathogenic	no assertion criteria provided
2042516	NM_005634.3(SOX3):c.946G>A (p.Gly316Ser)	SOX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
804090	NM_005634.3(SOX3):c.14G>C (p.Arg5Pro)	SOX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
95305	NM_005634.3(SOX3):c.735_737dup (p.Ala248dup)	SOX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805522	NM_005634.3(SOX3):c.253A>C (p.Lys85Gln)	LOC108281134	Uncertain significance	criteria provided, single submitter
1030001	NM_005634.3(SOX3):c.791T>G (p.Val264Gly)	SOX3	Uncertain significance	criteria provided, single submitter
1034197	NM_005634.3(SOX3):c.20A>G (p.Asn7Ser)	SOX3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1034198	NM_005634.3(SOX3):c.337G>A (p.Ala113Thr)	SOX3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1299871	NM_005634.3(SOX3):c.729_731dup (p.Ala248dup)	SOX3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2582418	NM_005634.3(SOX3):c.1265G>A (p.Arg422His)	SOX3	Uncertain significance	criteria provided, single submitter
3892530	NM_005634.3(SOX3):c.331G>A (p.Ala111Thr)	SOX3	Uncertain significance	criteria provided, single submitter
4819820	NM_005634.3(SOX3):c.1103G>A (p.Gly368Asp)	SOX3	Uncertain significance	criteria provided, single submitter
167718	NM_005634.3(SOX3):c.157G>C (p.Val53Leu)	LOC108281134	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
193320	NM_005634.3(SOX3):c.14G>A (p.Arg5Gln)	LOC108281134	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
289513	NM_005634.3(SOX3):c.711_731del (p.Ala242_Ala248del)	SOX3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 5 · 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
SOX3	Definitive	X-linked	intellectual disability, X-linked, with panhypopituitarism	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOX3	Orphanet:3157	Septo-optic dysplasia spectrum
SOX3	Orphanet:393	46,XX testicular difference of sex development
SOX3	Orphanet:67045	X-linked intellectual disability with isolated growth hormone deficiency
SOX3	Orphanet:79495	X-linked congenital generalized hypertrichosis
SOX3	Orphanet:90695	Non-acquired panhypopituitarism

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
SOX3	HGNC:11199	ENSG00000134595	P41225	Transcription factor SOX-3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOX3	Transcription factor SOX-3	Transcription factor required during the formation of the hypothalamo-pituitary axis.

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOX3	Transcription factor	no		HMG_box_dom, SOX_fam, HMG_box_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
embryo	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOX3	72	broad	marker	ventricular zone, ganglionic eminence, embryo

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOX3	47

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SOX3	P41225	58.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Deactivation of the beta-catenin transactivating complex	1	233.1×	0.012	SOX3
TCF dependent signaling in response to WNT	1	117.7×	0.012	SOX3
Signaling by WNT	1	112.0×	0.012	SOX3
Signal Transduction	1	10.2×	0.098	SOX3

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
sex determination	1	1685.2×	0.003	SOX3
hypothalamus development	1	1053.2×	0.003	SOX3
face development	1	802.5×	0.003	SOX3
sensory organ development	1	674.1×	0.003	SOX3
pituitary gland development	1	648.1×	0.003	SOX3
negative regulation of neuron differentiation	1	271.8×	0.007	SOX3
central nervous system development	1	115.4×	0.014	SOX3
neuron differentiation	1	100.3×	0.014	SOX3
brain development	1	79.5×	0.015	SOX3
negative regulation of transcription by RNA polymerase II	1	17.7×	0.062	SOX3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	SOX3

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
SOX3	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	SOX3

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)
SOX3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.