intellectual disability, X-linked 63

Summary

intellectual disability, X-linked 63 (MONDO:0010313) is a disease caused by ACSL4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ACSL4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 40

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked 63
Mondo ID	MONDO:0010313
MeSH	C564522
OMIM	300387
DOID	DOID:0112050
UMLS	C1845672
MedGen	337002
GARD	0005613
Is cancer (heuristic)	no

Also known as: ACSL4 non-syndromic X-linked intellectual disability · ACSL4-related intellectual disability · intellectual developmental disorder, X-linked 63, X-linked dominant · intellectual disability, X-linked 63 · intellectual disability, X-linked type 63 · mental retardation, X-linked 63 · mental retardation, X-linked 68 · mental retardation, X-linked type 63 · MRX63 · non-syndromic X-linked intellectual disability caused by mutation in ACSL4

Data availability: 40 ClinVar variants · 4 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 › non-syndromic X-linked intellectual disability › intellectual disability, X-linked 63

Related subtypes (51): intellectual disability, X-linked 23, intellectual disability, X-linked 20, intellectual disability, X-linked 14, intellectual disability, X-linked 50, intellectual disability, X-linked 21, intellectual disability, X-linked 58, intellectual disability, X-linked 72, intellectual disability, X-linked 53, intellectual disability, X-linked 73, intellectual disability, X-linked 42, intellectual disability, X-linked, with or without seizures, ARX-related, intellectual disability, X-linked 2, intellectual disability, X-linked 81, intellectual disability, X-linked 46, intellectual disability, X-linked 77, intellectual disability, X-linked 45, intellectual disability, X-linked 84, intellectual disability, X-linked 82, intellectual disability, X-linked 30, intellectual disability, X-linked 91, intellectual disability, X-linked 93, chromosome Xp11.22 duplication syndrome, intellectual disability, X-linked 95, intellectual disability, X-linked 96, intellectual disability, X-linked 97, intellectual disability, X-linked 19, intellectual disability, X-linked 89, intellectual disability, X-linked 41, intellectual disability, X-linked 90, intellectual disability, X-linked 92, intellectual disability, X-linked 88, intellectual disability, X-linked 99, intellectual disability, X-linked 100, intellectual disability, X-linked 101, intellectual disability, X-linked 102, intellectual disability, X-linked 61, intellectual disability, X-linked 103, intellectual disability, X-linked 104, intellectual disability, X-linked 105, intellectual disability, X-linked 1, methylmalonic acidemia with homocystinuria, type cblX, FRAXE intellectual disability, intellectual disability, X-linked 9, intellectual developmental disorder, X-linked 108, intellectual disability, X-linked 106, intellectual disability, X-linked 107, intellectual developmental disorder, X-linked 110, intellectual developmental disorder, X-linked 111, intellectual developmental disorder, X-linked 112, intellectual developmental disorder, X-linked 113, intellectual developmental disorder, X-linked 114

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

40 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 7 likely pathogenic, 4 pathogenic, 2 conflicting classifications of pathogenicity, 1 benign, 1 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11564	NM_001318510.2(ACSL4):c.1585C>A (p.Arg529Ser)	ACSL4	Pathogenic	no assertion criteria provided
11565	NM_001318510.2(ACSL4):c.1003-2A>G	ACSL4	Pathogenic	no assertion criteria provided
1675197	NM_001318510.2(ACSL4):c.802del (p.Leu268fs)	ACSL4	Pathogenic	criteria provided, single submitter
3382992	NM_001318510.2(ACSL4):c.1235dup (p.Met413fs)	ACSL4	Pathogenic	criteria provided, single submitter
11566	NM_001318510.2(ACSL4):c.1001C>T (p.Pro334Leu)	ACSL4	Likely pathogenic	criteria provided, single submitter
1691846	NM_001318510.2(ACSL4):c.1653_1654insT (p.Lys552Ter)	ACSL4	Likely pathogenic	criteria provided, single submitter
1709879	NM_001318510.2(ACSL4):c.1072_1073del (p.Leu358fs)	ACSL4	Likely pathogenic	criteria provided, single submitter
1710150	NM_001318510.2(ACSL4):c.257del (p.Asn86fs)	ACSL4	Likely pathogenic	no assertion criteria provided
3362695	NM_001318510.2(ACSL4):c.1315+1G>A	ACSL4	Likely pathogenic	criteria provided, single submitter
3777030	NM_001318510.2(ACSL4):c.629_630insC (p.Glu210fs)	ACSL4	Likely pathogenic	criteria provided, single submitter
975171	NM_001318510.2(ACSL4):c.473C>A (p.Ser158Tyr)	ACSL4	Likely pathogenic	no assertion criteria provided
1338218	NM_001318510.2(ACSL4):c.90A>G (p.Ile30Met)	ACSL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
633031	NM_001318510.2(ACSL4):c.1586G>A (p.Arg529His)	ACSL4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1213768	NM_001318510.2(ACSL4):c.1417A>G (p.Asn473Asp)	ACSL4	Uncertain significance	criteria provided, single submitter
1314174	NM_001318510.2(ACSL4):c.812A>G (p.Lys271Arg)	ACSL4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1325550	NM_001318510.2(ACSL4):c.1502C>A (p.Ser501Tyr)	ACSL4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1332791	NM_001318510.2(ACSL4):c.151AAG[1] (p.Lys52del)	ACSL4	Uncertain significance	criteria provided, single submitter
1695311	NM_001318510.2(ACSL4):c.386G>C (p.Cys129Ser)	ACSL4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1696650	NM_001318510.2(ACSL4):c.1698-3dup	ACSL4	Uncertain significance	criteria provided, single submitter
1805575	NM_001318510.2(ACSL4):c.468G>T (p.Glu156Asp)	ACSL4	Uncertain significance	criteria provided, single submitter
2438828	NM_001318510.2(ACSL4):c.1028A>C (p.Asn343Thr)	ACSL4	Uncertain significance	criteria provided, single submitter
2438829	NM_001318510.2(ACSL4):c.805G>T (p.Gly269Ter)	ACSL4	Uncertain significance	criteria provided, single submitter
2442101	NM_001318510.2(ACSL4):c.-10G>T	ACSL4	Uncertain significance	criteria provided, single submitter
2582432	NM_001318510.2(ACSL4):c.1846G>T (p.Ala616Ser)	ACSL4	Uncertain significance	criteria provided, single submitter
2661913	NM_001318510.2(ACSL4):c.1450A>C (p.Asn484His)	ACSL4	Uncertain significance	no assertion criteria provided
3238777	NM_001318510.2(ACSL4):c.1051A>G (p.Met351Val)	ACSL4	Uncertain significance	criteria provided, single submitter
3255102	NM_001318510.2(ACSL4):c.67C>T (p.His23Tyr)	ACSL4	Uncertain significance	criteria provided, single submitter
3359030	NM_001318510.2(ACSL4):c.1001del (p.Pro334fs)	ACSL4	Uncertain significance	criteria provided, single submitter
3382588	NM_001318510.2(ACSL4):c.1143G>T (p.Leu381=)	ACSL4	Uncertain significance	criteria provided, single submitter
3382727	NM_001318510.2(ACSL4):c.1051dup (p.Met351fs)	ACSL4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
ACSL4	Strong	X-linked	intellectual disability, X-linked 63	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACSL4	Orphanet:777	X-linked non-syndromic intellectual disability
ACSL4	Orphanet:86818	Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis 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
ACSL4	HGNC:3571	ENSG00000068366	O60488	Long-chain-fatty-acid–CoA ligase 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACSL4	Long-chain-fatty-acid–CoA ligase 4	Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoA for both synthesis of cellular lipids, and degradation via beta-oxidation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACSL4	Enzyme (other)	yes	6.2.1.15	AMP-dep_synth/lig_dom, AMP-binding_CS, ANL_N_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
adrenal tissue	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACSL4	268	ubiquitous	marker	adrenal tissue, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACSL4	3,040

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACSL4	O60488	90.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Free fatty acids regulate insulin secretion	1	3806.7×	0.001	ACSL4
Intracellular metabolism of fatty acids regulates insulin secretion	1	3806.7×	0.001	ACSL4
Synthesis of very long-chain fatty acyl-CoAs	1	456.8×	0.005	ACSL4
Fatty acyl-CoA biosynthesis	1	439.2×	0.005	ACSL4
Regulation of insulin secretion	1	219.6×	0.008	ACSL4
Integration of energy metabolism	1	175.7×	0.009	ACSL4
Fatty acid metabolism	1	131.3×	0.010	ACSL4
Metabolism of lipids	1	31.6×	0.036	ACSL4
Metabolism	1	11.6×	0.086	ACSL4

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
negative regulation of prostaglandin secretion	1	16852.0×	9e-04	ACSL4
long-chain fatty-acyl-CoA metabolic process	1	2407.4×	0.002	ACSL4
embryonic process involved in female pregnancy	1	2106.5×	0.002	ACSL4
positive regulation of ferroptosis	1	1532.0×	0.002	ACSL4
lipid biosynthetic process	1	991.3×	0.003	ACSL4
alpha-linolenic acid metabolic process	1	887.0×	0.003	ACSL4
long-chain fatty-acyl-CoA biosynthetic process	1	842.6×	0.003	ACSL4
unsaturated fatty acid biosynthetic process	1	648.1×	0.003	ACSL4
long-chain fatty acid metabolic process	1	624.1×	0.003	ACSL4
long-chain fatty acid biosynthetic process	1	443.5×	0.003	ACSL4
positive regulation of insulin secretion	1	255.3×	0.005	ACSL4
fatty acid metabolic process	1	193.7×	0.006	ACSL4
positive regulation of cell growth	1	183.2×	0.006	ACSL4
neuron differentiation	1	100.3×	0.011	ACSL4
lipid metabolic process	1	91.6×	0.011	ACSL4

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
ACSL4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ACSL4	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACSL4	6.2.1.15, 6.2.1.3	arachidonate-CoA ligase, long-chain-fatty-acid-CoA ligase

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	1	ACSL4
E	Difficult family or no structure, no drug	0

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)
ACSL4	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.