Intellectual disability, autosomal dominant 42

Summary

Intellectual disability, autosomal dominant 42 (MONDO:0014855) is a disease caused by GNB1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GNB1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 65
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		26	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001290	Generalized hypotonia	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0002474	Expressive language delay	Frequent (30-79%)
HP:0010841	Multifocal epileptiform discharges	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002384	Focal impaired awareness seizure	Occasional (5-29%)
HP:0002509	Limb hypertonia	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0007772	Impaired smooth pursuit	Occasional (5-29%)
HP:0008947	Floppy infant	Occasional (5-29%)
HP:0011198	EEG with generalized epileptiform discharges	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0000252	Microcephaly	Excluded (0%)
HP:0000396	Overfolded helix	Very rare (<1-4%)
HP:0000767	Pectus excavatum	Very rare (<1-4%)
HP:0002126	Polymicrogyria	Very rare (<1-4%)
HP:0012448	Delayed myelination	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 42
Mondo ID	MONDO:0014855
OMIM	616973
Orphanet	488613
DOID	DOID:0070072
UMLS	C4310774
MedGen	934741
GARD	0018501
Is cancer (heuristic)	no

Also known as: autosomal dominant intellectual disability 42 · autosomal dominant non-syndromic intellectual disability 42 · autosomal dominant non-syndromic intellectual disability caused by mutation in GNB1 · global developmental delay-neuro-ophthalmological abnormalities-seizures-intellectual disability syndrome · GNB1 autosomal dominant non-syndromic intellectual disability · GNB1-related disorder · GNB1-related neurodevelopmental disorder · intellectual developmental disorder, autosomal dominant 42 · intellectual disability, autosomal dominant 42 · intellectual disability, autosomal dominant type 42 · mental retardation, autosomal dominant 42 · mental retardation, autosomal dominant type 42 · MRD42

Data availability: 65 ClinVar variants · 6 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › intellectual disability, autosomal dominant › intellectual disability, autosomal dominant 42

Related subtypes (28): intellectual disability, autosomal dominant 1, intellectual disability, autosomal dominant 3, intellectual disability, autosomal dominant 4, intellectual disability, autosomal dominant 5, intellectual disability, autosomal dominant 6, intellectual disability, autosomal dominant 2, neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, intellectual disability, autosomal dominant 9, intellectual disability, autosomal dominant 10, intellectual disability, autosomal dominant 11, intellectual disability, autosomal dominant 24, intellectual disability, autosomal dominant 38, intellectual disability, autosomal dominant 39, intellectual disability, autosomal dominant 40, autosomal dominant non-syndromic intellectual disability, intellectual developmental disorder, autosomal dominant 65, intellectual developmental disorder, autosomal dominant 69, intellectual developmental disorder, autosomal dominant 66, intellectual developmental disorder, autosomal dominant 64, intellectual developmental disorder, autosomal dominant 67, intellectual developmental disorder, autosomal dominant 68, autosomal dominant syndromic intellectual disability, intellectual developmental disorder, autosomal dominant 70, intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities, intellectual developmental disorder, autosomal dominant 72, intellectual developmental disorder, autosomal dominant 74, intellectual developmental disorder, autosomal dominant 75, intellectual developmental disorder, autosomal dominant 76

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

65 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 15 pathogenic, 12 pathogenic/likely pathogenic, 11 likely pathogenic, 8 conflicting classifications of pathogenicity, 1 likely benign, 1 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1315576	NM_002074.5(GNB1):c.268-1G>T	GNB1	Pathogenic	no assertion criteria provided
1315577	NM_002074.5(GNB1):c.272_275del (p.His91fs)	GNB1	Pathogenic	no assertion criteria provided
1315578	NM_002074.5(GNB1):c.915_916del (p.Gly306fs)	GNB1	Pathogenic	no assertion criteria provided
1315579	NM_002074.5(GNB1):c.917-1G>T	GNB1	Pathogenic	no assertion criteria provided
1315581	NM_002074.5(GNB1):c.341G>A (p.Cys114Tyr)	GNB1	Pathogenic	no assertion criteria provided
1315582	NM_002074.5(GNB1):c.230G>T (p.Gly77Val)	GNB1	Pathogenic	criteria provided, single submitter
1518601	NM_002074.5(GNB1):c.217G>T (p.Ala73Ser)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699320	NM_002074.5(GNB1):c.228T>A (p.Asp76Glu)	GNB1	Pathogenic	criteria provided, single submitter
1700090	NM_002074.5(GNB1):c.229G>T (p.Gly77Cys)	GNB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1708250	NM_002074.5(GNB1):c.217G>A (p.Ala73Thr)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208722	NM_002074.5(GNB1):c.239T>C (p.Ile80Thr)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224711	NM_002074.5(GNB1):c.227A>G (p.Asp76Gly)	GNB1	Pathogenic	criteria provided, multiple submitters, no conflicts
224713	NM_002074.5(GNB1):c.229G>A (p.Gly77Ser)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224714	NM_002074.5(GNB1):c.233A>G (p.Lys78Arg)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224715	NM_002074.5(GNB1):c.239T>A (p.Ile80Asn)	GNB1	Pathogenic	criteria provided, multiple submitters, no conflicts
224716	NM_002074.5(GNB1):c.284T>C (p.Leu95Pro)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224717	NM_002074.5(GNB1):c.301A>G (p.Met101Val)	GNB1	Pathogenic	criteria provided, multiple submitters, no conflicts
2742218	NM_002074.5(GNB1):c.299_327del (p.Val100fs)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775807	NM_002074.5(GNB1):c.229G>C (p.Gly77Arg)	GNB1	Pathogenic	criteria provided, single submitter
391609	NM_002074.5(GNB1):c.239T>G (p.Ile80Ser)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
452797	NM_002074.5(GNB1):c.388G>A (p.Glu130Lys)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
521213	NM_002074.5(GNB1):c.353A>G (p.Asp118Gly)	GNB1	Pathogenic	criteria provided, multiple submitters, no conflicts
633546	NM_002074.5(GNB1):c.274G>A (p.Ala92Thr)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812755	NM_002074.5(GNB1):c.352G>T (p.Asp118Tyr)	GNB1	Pathogenic	criteria provided, multiple submitters, no conflicts
976696	NM_002074.5(GNB1):c.226G>A (p.Asp76Asn)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
985590	NM_002074.5(GNB1):c.230G>A (p.Gly77Asp)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
995962	NM_002074.5(GNB1):c.287G>T (p.Arg96Leu)	GNB1	Pathogenic	no assertion criteria provided
1048759	NM_002074.5(GNB1):c.496T>C (p.Cys166Arg)	GNB1	Likely pathogenic	no assertion criteria provided
1710142	NM_002074.5(GNB1):c.326G>A (p.Gly109Glu)	GNB1	Likely pathogenic	no assertion criteria provided
224718	NM_002074.5(GNB1):c.976G>A (p.Ala326Thr)	GNB1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
GNB1	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 42	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNB1	Orphanet:488613	Global developmental delay-neuro-ophthalmological abnormalities-seizures-intellectual disability 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
GNB1	HGNC:4396	ENSG00000078369	P62873	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNB1	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems.

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)
GNB1	Scaffold/PPI	no		WD40_G-protein_beta-like, WD40_rpt, WD40/YVTN_repeat-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
cortical plate	1
ganglionic eminence	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNB1	295	ubiquitous	marker	cortical plate, ganglionic eminence, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNB1	774

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNB1	P62873	1,262

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. 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
Activation of the phototransduction cascade	1	951.7×	0.005	GNB1
G beta:gamma signalling through BTK	1	634.4×	0.005	GNB1
Prostacyclin signalling through prostacyclin receptor	1	601.0×	0.005	GNB1
G beta:gamma signalling through PLC beta	1	571.0×	0.005	GNB1
G beta:gamma signalling through CDC42	1	571.0×	0.005	GNB1
Presynaptic function of Kainate receptors	1	543.8×	0.005	GNB1
Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	1	519.1×	0.005	GNB1
ADP signalling through P2Y purinoceptor 12	1	496.5×	0.005	GNB1
G-protein activation	1	475.8×	0.005	GNB1
Thromboxane signalling through TP receptor	1	475.8×	0.005	GNB1
ADP signalling through P2Y purinoceptor 1	1	456.8×	0.005	GNB1
G beta:gamma signalling through PI3Kgamma	1	439.2×	0.005	GNB1
Activation of G protein gated Potassium channels	1	393.8×	0.005	GNB1
Adrenaline,noradrenaline inhibits insulin secretion	1	393.8×	0.005	GNB1
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	393.8×	0.005	GNB1
Thrombin signalling through proteinase activated receptors (PARs)	1	356.9×	0.005	GNB1
Glucagon signaling in metabolic regulation	1	346.1×	0.005	GNB1
Glucagon-type ligand receptors	1	346.1×	0.005	GNB1
Inactivation, recovery and regulation of the phototransduction cascade	1	317.2×	0.005	GNB1
Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding	1	300.5×	0.005	GNB1
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	278.5×	0.005	GNB1
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	265.6×	0.005	GNB1
Vasopressin regulates renal water homeostasis via Aquaporins	1	265.6×	0.005	GNB1
ADORA2B mediated anti-inflammatory cytokines production	1	253.8×	0.005	GNB1
GPER1 signaling	1	248.3×	0.005	GNB1
G alpha (z) signalling events	1	233.1×	0.006	GNB1
Ca2+ pathway	1	178.4×	0.007	GNB1
Extra-nuclear estrogen signaling	1	170.4×	0.007	GNB1
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	160.8×	0.007	GNB1
Olfactory Signaling Pathway	1	144.6×	0.008	GNB1

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
cellular response to catecholamine stimulus	1	2407.4×	0.003	GNB1
adenylate cyclase-activating dopamine receptor signaling pathway	1	1532.0×	0.003	GNB1
sensory perception of taste	1	1123.5×	0.003	GNB1
G protein-coupled acetylcholine receptor signaling pathway	1	1053.2×	0.003	GNB1
cellular response to prostaglandin E stimulus	1	842.6×	0.003	GNB1
retina development in camera-type eye	1	255.3×	0.007	GNB1
Ras protein signal transduction	1	205.5×	0.008	GNB1
phospholipase C-activating G protein-coupled receptor signaling pathway	1	131.7×	0.010	GNB1
cell population proliferation	1	102.8×	0.012	GNB1
G protein-coupled receptor signaling pathway	1	36.2×	0.030	GNB1
signal transduction	1	16.1×	0.062	GNB1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GNB1	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMINOQUINURIDE	2	GNB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GNB1	12	Binding:12

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)
AMINOQUINURIDE	2	GNB1

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	1	GNB1
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.