Intellectual disability, autosomal recessive 43

Summary

Intellectual disability, autosomal recessive 43 (MONDO:0014354) is a disease caused by WASHC4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: WASHC4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 27

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal recessive 43
Mondo ID	MONDO:0014354
OMIM	615817
DOID	DOID:0081207
UMLS	C4014386
MedGen	862823
GARD	0022565
Is cancer (heuristic)	no

Also known as: autosomal recessive non-syndromic intellectual disability caused by mutation in WASHC4 · intellectual developmental disorder, autosomal recessive 43 · intellectual disability, autosomal recessive 43 · intellectual disability, autosomal recessive type 43 · mental retardation, autosomal recessive 43 · mental retardation, autosomal recessive type 43 · MRT43 · WASHC4 autosomal recessive non-syndromic intellectual disability

Data availability: 27 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 › non-syndromic intellectual disability › autosomal recessive non-syndromic intellectual disability › intellectual disability, autosomal recessive 43

Related subtypes (67): intellectual disability, autosomal recessive 1, intellectual disability, autosomal recessive 2, intellectual disability, autosomal recessive 3, intellectual disability, autosomal recessive 12, intellectual disability, autosomal recessive 5, intellectual disability, autosomal recessive 6, intellectual disability, autosomal recessive 7, intellectual disability, autosomal recessive 9, intellectual disability, autosomal recessive 10, intellectual disability, autosomal recessive 11, intellectual disability, autosomal recessive 4, intellectual disability, autosomal recessive 13, intellectual disability, autosomal recessive 14, Rafiq syndrome, intellectual disability, autosomal recessive 16, intellectual disability, autosomal recessive 18, intellectual disability, autosomal recessive 31, intellectual disability, autosomal recessive 29, intellectual disability, autosomal recessive 27, intellectual disability, autosomal recessive 33, intellectual disability, autosomal recessive 30, intellectual disability, autosomal recessive 19, intellectual disability, autosomal recessive 23, intellectual disability, autosomal recessive 24, intellectual disability, autosomal recessive 25, intellectual disability, autosomal recessive 28, intellectual disability, autosomal recessive 34, intellectual disability, autosomal recessive 42, intellectual disability, autosomal recessive 44, intellectual disability, autosomal recessive 45, intellectual disability, autosomal recessive 46, intellectual disability, autosomal recessive 47, Al-Raqad syndrome, intellectual disability, autosomal recessive 50, intellectual disability, autosomal recessive 51, intellectual disability, autosomal recessive 52, intellectual disability, autosomal recessive 54, intellectual disability, autosomal recessive 56, intellectual developmental disorder, autosomal recessive 74, intellectual disability, autosomal recessive 57, intellectual disability, autosomal recessive 58, intellectual disability, autosomal recessive 59, pontocerebellar hypoplasia type 1, intellectual disability, autosomal recessive 64, intellectual disability, autosomal recessive 65, intellectual developmental disorder, autosomal recessive 73, intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, intellectual disability, autosomal recessive 61, intellectual developmental disorder, autosomal recessive 76, intellectual developmental disorder, autosomal recessive 77, intellectual disability, autosomal recessive 66, intellectual developmental disorder, autosomal recessive 67, intellectual developmental disorder, autosomal recessive 68, intellectual developmental disorder, autosomal recessive 69, intellectual developmental disorder, autosomal recessive 70, intellectual developmental disorder, autosomal recessive 71, intellectual developmental disorder, autosomal recessive 72, glycosylphosphatidylinositol biosynthesis defect 16, intellectual disability, autosomal recessive 60, intellectual disability, autosomal recessive 63, adenosine kinase deficiency, intellectual developmental disorder, autosomal recessive 78, intellectual developmental disorder, autosomal recessive 79, intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, intellectual developmental disorder, autosomal recessive 81, intellectual developmental disorder, autosomal recessive 82, intellectual developmental disorder, autosomal recessive 83

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

27 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 9 likely pathogenic, 4 conflicting classifications of pathogenicity, 3 pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
133296	NM_015275.3(WASHC4):c.3056C>G (p.Pro1019Arg)	WASHC4	Pathogenic	no assertion criteria provided
1697335	NM_015275.3(WASHC4):c.1324C>T (p.Gln442Ter)	WASHC4	Pathogenic	no assertion criteria provided
1697336	NM_015275.3(WASHC4):c.3143A>G (p.Asp1048Gly)	WASHC4	Pathogenic	no assertion criteria provided
1804867	NM_015275.3(WASHC4):c.1374del (p.Met458fs)	WASHC4	Likely pathogenic	criteria provided, single submitter
1878289	NM_015275.3(WASHC4):c.2133dup (p.Ser712fs)	WASHC4	Likely pathogenic	criteria provided, single submitter
3376285	NM_015275.3(WASHC4):c.1786C>T (p.Arg596Ter)	WASHC4	Likely pathogenic	criteria provided, single submitter
4292949	NM_015275.3(WASHC4):c.1666C>T (p.Arg556Ter)	WASHC4	Likely pathogenic	criteria provided, single submitter
4531378	NM_015275.3(WASHC4):c.2556dup (p.Phe853fs)	WASHC4	Likely pathogenic	criteria provided, single submitter
4845750	NM_015275.3(WASHC4):c.2944C>T (p.Arg982Ter)	WASHC4	Likely pathogenic	criteria provided, single submitter
4845761	NM_015275.3(WASHC4):c.2611C>T (p.Arg871Ter)	WASHC4	Likely pathogenic	criteria provided, single submitter
695111	NM_015275.3(WASHC4):c.3236A>G (p.Lys1079Arg)	WASHC4	Likely pathogenic	criteria provided, single submitter
996910	NM_015275.3(WASHC4):c.1038+1G>T	WASHC4	Likely pathogenic	criteria provided, single submitter
742318	NM_015275.3(WASHC4):c.49G>A (p.Asp17Asn)	LOC130008643	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3362164	NM_015275.3(WASHC4):c.3334C>T (p.Arg1112Ter)	WASHC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
695112	NM_015275.3(WASHC4):c.1508A>G (p.His503Arg)	WASHC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
872777	NM_015275.3(WASHC4):c.3041A>G (p.Tyr1014Cys)	WASHC4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029530	NM_015275.3(WASHC4):c.971T>C (p.Leu324Ser)	WASHC4	Uncertain significance	criteria provided, single submitter
1032672	NM_015275.3(WASHC4):c.2767A>G (p.Met923Val)	WASHC4	Uncertain significance	criteria provided, single submitter
1032674	NM_015275.3(WASHC4):c.443C>G (p.Ser148Cys)	WASHC4	Uncertain significance	criteria provided, single submitter
1032675	NM_015275.3(WASHC4):c.641A>G (p.Lys214Arg)	WASHC4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1098606	NM_015275.3(WASHC4):c.154T>G (p.Ser52Ala)	WASHC4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1098607	NM_015275.3(WASHC4):c.2423G>A (p.Arg808Gln)	WASHC4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2584684	NM_015275.3(WASHC4):c.1731del (p.Pro579fs)	WASHC4	Uncertain significance	no assertion criteria provided
2690444	NM_015275.3(WASHC4):c.3420G>A (p.Ala1140=)	WASHC4	Uncertain significance	criteria provided, single submitter
2690445	NM_015275.3(WASHC4):c.1643A>G (p.Asn548Ser)	WASHC4	Uncertain significance	criteria provided, single submitter
4292458	NM_015275.3(WASHC4):c.2759-1539del	WASHC4	Uncertain significance	criteria provided, single submitter
1300067	NM_015275.3(WASHC4):c.2701G>A (p.Val901Ile)	WASHC4	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
WASHC4	Strong	Autosomal recessive	intellectual disability, autosomal recessive 43	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WASHC4	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability

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
WASHC4	HGNC:29174	ENSG00000136051	Q2M389	WASH complex subunit 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WASHC4	WASH complex subunit 4	Acts as a component of the WASH core complex that functions as a nucleation-promoting factor (NPF) at the surface of endosomes, where it recruits and activates the Arp2/3 complex to induce actin polymerization, playing a key role in the fi…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
WASHC4	Other/Unknown	no		WASH7, WASH-4_N, WASH-7_central

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
calcaneal tendon	1
mammary duct	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WASHC4	296	ubiquitous	marker	secondary oocyte, calcaneal tendon, mammary duct

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WASHC4	1,434

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WASHC4	Q2M389	83.82

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
nuclear envelope budding	1	16852.0×	3e-04	WASHC4
endolysosomal toll-like receptor signaling pathway	1	16852.0×	3e-04	WASHC4
regulation of Arp2/3 complex-mediated actin nucleation	1	1053.2×	0.002	WASHC4
regulation of protein complex stability	1	1053.2×	0.002	WASHC4
neuromuscular process	1	526.6×	0.003	WASHC4
endosome organization	1	374.5×	0.004	WASHC4
cognition	1	285.6×	0.005	WASHC4
endosomal transport	1	244.2×	0.005	WASHC4
protein transport	1	43.9×	0.023	WASHC4

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
WASHC4	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
WASHC4	1	Binding:1

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	WASHC4

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)
WASHC4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.