Intellectual disability, autosomal dominant 46

Summary

Intellectual disability, autosomal dominant 46 (MONDO:0030911) is a disease caused by KCNQ5 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: KCNQ5 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 75

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 46
Mondo ID	MONDO:0030911
OMIM	617601
DOID	DOID:0080237
UMLS	C4539851
MedGen	1618560
GARD	0025659
Is cancer (heuristic)	no

Also known as: autosomal dominant mental retardation 46 · intellectual disability, autosomal dominant 46 · mental retardation, autosomal dominant 46 · MRD46

Data availability: 75 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › autosomal dominant non-syndromic intellectual disability › intellectual disability, autosomal dominant 46

Related subtypes (25): intellectual disability, autosomal dominant 22, neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language, intellectual disability, autosomal dominant 33, intellectual disability, autosomal dominant 34, intellectual disability, autosomal dominant 41, intellectual disability, autosomal dominant 43, intellectual disability, autosomal dominant 58, intellectual disability, autosomal dominant 45, intellectual disability, autosomal dominant 47, Clark-Baraitser syndrome, intellectual disability, autosomal dominant 50, intellectual disability, autosomal dominant 51, intellectual disability, autosomal dominant 52, intellectual disability, autosomal dominant 53, intellectual disability, autosomal dominant 54, intellectual disability, autosomal dominant 55, with seizures, intellectual disability, autosomal dominant 56, intellectual developmental disorder 61, intellectual developmental disorder 59, intellectual developmental disorder 60 with seizures, intellectual developmental disorder 62, intellectual developmental disorder, autosomal dominant 63, with macrocephaly, Coffin-Siris syndrome 6, intellectual disability, autosomal dominant 57, intellectual developmental disorder, autosomal dominant 73

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

75 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 14 conflicting classifications of pathogenicity, 9 pathogenic, 8 likely pathogenic, 2 benign, 2 benign/likely benign, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1675172	NM_019842.4(KCNQ5):c.824dup (p.Leu275fs)	KCNQ5	Pathogenic	criteria provided, single submitter
2876968	NM_019842.4(KCNQ5):c.739C>T (p.Arg247Ter)	KCNQ5	Pathogenic	criteria provided, multiple submitters, no conflicts
3381895	NM_019842.4(KCNQ5):c.966G>A (p.Trp322Ter)	KCNQ5	Pathogenic	criteria provided, single submitter
431385	NM_019842.4(KCNQ5):c.434T>G (p.Val145Gly)	KCNQ5	Pathogenic	no assertion criteria provided
431386	NM_019842.4(KCNQ5):c.1021C>A (p.Leu341Ile)	KCNQ5	Pathogenic	no assertion criteria provided
431387	NM_019842.4(KCNQ5):c.1286G>T (p.Ser429Ile)	KCNQ5	Pathogenic	criteria provided, single submitter
431388	NM_019842.4(KCNQ5):c.1106C>G (p.Pro369Arg)	KCNQ5	Pathogenic	no assertion criteria provided
521362	NM_019842.4(KCNQ5):c.1105C>A (p.Pro369Thr)	KCNQ5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523807	NM_019842.4(KCNQ5):c.532C>T (p.Arg178Ter)	KCNQ5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802242	NM_019842.4(KCNQ5):c.1106C>A (p.Pro369Gln)	KCNQ5	Pathogenic	criteria provided, single submitter
975567	NM_019842.4(KCNQ5):c.1040G>C (p.Gly347Ala)	KCNQ5	Pathogenic	criteria provided, single submitter
2500718	NM_019842.4(KCNQ5):c.545C>T (p.Ala182Val)	KCNQ5	Likely pathogenic	criteria provided, single submitter
2775437	NM_019842.4(KCNQ5):c.1667G>C (p.Gly556Ala)	KCNQ5	Likely pathogenic	criteria provided, single submitter
3220891	NM_019842.4(KCNQ5):c.273del (p.Lys92fs)	KCNQ5	Likely pathogenic	criteria provided, single submitter
3572863	NM_019842.4(KCNQ5):c.1408C>T (p.Arg470Ter)	KCNQ5	Likely pathogenic	criteria provided, single submitter
4074723	NM_019842.4(KCNQ5):c.1631A>G (p.Tyr544Cys)	KCNQ5	Likely pathogenic	criteria provided, single submitter
4077061	NM_019842.4(KCNQ5):c.1051G>T (p.Ala351Ser)	KCNQ5	Likely pathogenic	criteria provided, single submitter
984630	NM_019842.4(KCNQ5):c.1291A>T (p.Arg431Trp)	KCNQ5	Likely pathogenic	no assertion criteria provided
988749	NM_019842.4(KCNQ5):c.875A>G (p.Asn292Ser)	KCNQ5	Likely pathogenic	no assertion criteria provided
1033745	NM_019842.4(KCNQ5):c.1575C>A (p.Ile525=)	KCNQ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1064571	NM_019842.4(KCNQ5):c.2228del (p.Ala743fs)	KCNQ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1341834	NM_019842.4(KCNQ5):c.2726G>A (p.Arg909Gln)	KCNQ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1467646	NM_019842.4(KCNQ5):c.2444T>G (p.Leu815Arg)	KCNQ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1551116	NM_019842.4(KCNQ5):c.68CGG[7] (p.Ala26_Ala27dup)	KCNQ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1685901	NM_019842.4(KCNQ5):c.730C>T (p.Arg244Cys)	KCNQ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1721189	NM_019842.4(KCNQ5):c.1076G>A (p.Arg359His)	KCNQ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2090080	NM_019842.4(KCNQ5):c.1915C>T (p.Leu639Phe)	KCNQ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2982623	NM_019842.4(KCNQ5):c.8G>T (p.Arg3Leu)	KCNQ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
931884	NM_019842.4(KCNQ5):c.2478G>C (p.Leu826Phe)	KCNQ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
977399	NM_019842.4(KCNQ5):c.2354T>C (p.Val785Ala)	KCNQ5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 4 · 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
KCNQ5	Strong	Autosomal dominant	intellectual disability, autosomal dominant 46	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNQ5	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
HSPB8	Orphanet:139525	Distal hereditary motor neuropathy type 2
HSPB8	Orphanet:476093	HSPB8-related autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome
HSPB8	Orphanet:99945	Autosomal dominant Charcot-Marie-Tooth disease type 2L

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
KCNQ5	HGNC:6299	ENSG00000185760	Q9NR82	Potassium voltage-gated channel subfamily KQT member 5	gencc,clinvar
HSPB8	HGNC:30171	ENSG00000152137	Q9UJY1	Heat shock protein beta-8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNQ5	Potassium voltage-gated channel subfamily KQT member 5	Pore-forming subunit of the voltage-gated potassium (Kv) channel broadly expressed in brain and involved in the regulation of neuronal excitability.
HSPB8	Heat shock protein beta-8	Involved in the chaperone-assisted selective autophagy (CASA), a crucial process for protein quality control, particularly in mechanical strained cells and tissues such as muscle.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Ion channel	1	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNQ5	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCNQ_C
HSPB8	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone

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
Brodmann (1909) area 23	1
endothelial cell	1
pons	1
gastrocnemius	1
mucosa of stomach	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNQ5	177	ubiquitous	marker	endothelial cell, pons, Brodmann (1909) area 23
HSPB8	284	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, mucosa of stomach, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNQ5	2,224
HSPB8	1,916

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNQ5	Q9NR82	5
HSPB8	Q9UJY1	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
HSF1-dependent transactivation	1	158.6×	0.016	HSPB8
Voltage gated Potassium channels	1	121.5×	0.016	KCNQ5
Potassium Channels	1	67.2×	0.020	KCNQ5
Neuronal System	1	22.1×	0.045	KCNQ5

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
positive regulation of aggrephagy	1	1404.3×	0.002	HSPB8
cellular response to unfolded protein	1	495.6×	0.003	HSPB8
potassium ion transmembrane transport	1	68.0×	0.015	KCNQ5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
KCNQ5	EZOGABINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNQ5	2	4
HSPB8	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EZOGABINE	4	KCNQ5
FLINDOKALNER	3	KCNQ5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNQ5	40	Binding:35, Functional:2, ADMET:2, Toxicity:1

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

2 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)
EZOGABINE	4	KCNQ5
FLINDOKALNER	3	KCNQ5

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNQ5
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	HSPB8

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)
HSPB8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.