Intellectual disability, autosomal recessive 44

Summary

Intellectual disability, autosomal recessive 44 (MONDO:0014409) is a disease caused by METTL23 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: METTL23 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 23

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal recessive 44
Mondo ID	MONDO:0014409
OMIM	615942
DOID	DOID:0081208
UMLS	C4014745
MedGen	863182
GARD	0022566
Is cancer (heuristic)	no

Also known as: autosomal recessive non-syndromic intellectual disability caused by mutation in METTL23 · intellectual disability, autosomal recessive 44 · intellectual disability, autosomal recessive type 44 · mental retardation, autosomal recessive 44 · mental retardation, autosomal recessive type 44 · METTL23 autosomal recessive non-syndromic intellectual disability · MRT44

Data availability: 23 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 › autosomal recessive non-syndromic intellectual disability › intellectual disability, autosomal recessive 44

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 43, 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

23 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 5 pathogenic, 4 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
144023	NM_001080510.5(METTL23):c.169_172del (p.His57fs)	METTL23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
144024	NM_001080510.5(METTL23):c.282_286del (p.Gln94fs)	METTL23	Pathogenic	no assertion criteria provided
144025	NM_001080510.5(METTL23):c.397C>T (p.Gln133Ter)	METTL23	Pathogenic	criteria provided, single submitter
1805314	NM_001080510.5(METTL23):c.322+2dup	METTL23	Pathogenic	criteria provided, single submitter
1810219	NM_001080510.5(METTL23):c.434_438del (p.Leu145fs)	METTL23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2582828	NM_001080510.5(METTL23):c.322+1del	METTL23	Pathogenic	criteria provided, single submitter
420567	NM_001080510.5(METTL23):c.470_471del (p.Leu157fs)	METTL23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812707	NM_001080510.5(METTL23):c.178dup (p.Glu60fs)	METTL23	Pathogenic	no assertion criteria provided
985456	NM_001080510.5(METTL23):c.174_177del (p.Cys58fs)	METTL23	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324716	NM_001080510.5(METTL23):c.126del (p.Lys42fs)	METTL23	Likely pathogenic	criteria provided, single submitter
1805419	NM_001080510.5(METTL23):c.409del (p.Ala137fs)	METTL23	Likely pathogenic	criteria provided, single submitter
3024257	NM_001080510.5(METTL23):c.204_207del (p.Met68fs)	METTL23	Likely pathogenic	criteria provided, single submitter
1031798	NM_001080510.5(METTL23):c.250A>G (p.Ile84Val)	METTL23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
435859	NM_001080510.5(METTL23):c.271C>G (p.Leu91Val)	METTL23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
520855	NM_001080510.5(METTL23):c.275CAC[1] (p.Pro93del)	METTL23	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031045	NM_001080510.5(METTL23):c.521G>T (p.Gly174Val)	METTL23	Uncertain significance	criteria provided, single submitter
1032598	NM_001080510.5(METTL23):c.319G>A (p.Glu107Lys)	METTL23	Uncertain significance	criteria provided, single submitter
1032599	NM_001080510.5(METTL23):c.417G>T (p.Trp139Cys)	METTL23	Uncertain significance	criteria provided, single submitter
1032600	NM_001080510.5(METTL23):c.496G>T (p.Asp166Tyr)	METTL23	Uncertain significance	criteria provided, single submitter
1065469	NM_001080510.5(METTL23):c.407+6T>C	METTL23	Uncertain significance	criteria provided, single submitter
1712311	NM_001080510.5(METTL23):c.266T>A (p.Leu89Gln)	METTL23	Uncertain significance	criteria provided, multiple submitters, no conflicts
3906856	NM_001080510.5(METTL23):c.302A>T (p.Asp101Val)	METTL23	Uncertain significance	no assertion criteria provided
520872	NM_001080510.5(METTL23):c.20C>T (p.Ala7Val)	METTL23	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
METTL23	Definitive	Autosomal recessive	intellectual disability, autosomal recessive 44	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
METTL23	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
METTL23	HGNC:26988	ENSG00000181038	Q86XA0	Histone-arginine methyltransferase METTL23	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
METTL23	Histone-arginine methyltransferase METTL23	Histone methyltransferase that dimethylates histone H3 at ‘Arg-17’, forming asymmetric dimethylarginine (H3R17me2a), leading to activate transcription via chromatin remodeling.

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)
METTL23	Other/Unknown	no		Methyltransf_16, SAM-dependent_MTases_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
epithelial cell of pancreas	1
kidney epithelium	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
METTL23	256	ubiquitous	marker	kidney epithelium, epithelial cell of pancreas, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
METTL23	722

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
METTL23	Q86XA0	93.81

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
Maternal to zygotic transition (MZT)	1	713.8×	0.006	METTL23
Replacement of protamines by nucleosomes in the male pronucleus	1	271.9×	0.007	METTL23
Chromatin modifications during the maternal to zygotic transition (MZT)	1	163.1×	0.008	METTL23
Developmental Biology	1	14.5×	0.069	METTL23

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
epigenetic programing of male pronucleus	1	4213.0×	0.001	METTL23
epigenetic programming in the zygotic pronuclei	1	1872.4×	0.002	METTL23
epigenetic regulation of gene expression	1	383.0×	0.005	METTL23
cognition	1	285.6×	0.005	METTL23
methylation	1	170.2×	0.007	METTL23
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	METTL23

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
METTL23	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	METTL23

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)
METTL23	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.