Intellectual disability, autosomal dominant 51

Summary

Intellectual disability, autosomal dominant 51 (MONDO:0030917) is a disease caused by KMT5B (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: KMT5B (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 75

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 51
Mondo ID	MONDO:0030917
OMIM	617788
Orphanet	684226
DOID	DOID:0080232
UMLS	C4540474
MedGen	1625009
GARD	0025662
Is cancer (heuristic)	no

Also known as: autosomal dominant mental retardation 51 · intellectual disability, autosomal dominant 51 · mental retardation, autosomal dominant 51 · MRD51

Data availability: 75 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 dominant non-syndromic intellectual disability › intellectual disability, autosomal dominant 51

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 46, intellectual disability, autosomal dominant 47, Clark-Baraitser syndrome, intellectual disability, autosomal dominant 50, 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:

31 uncertain significance, 19 pathogenic, 15 likely pathogenic, 5 pathogenic/likely pathogenic, 2 likely benign, 2 conflicting classifications of pathogenicity, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1164062	NM_017635.5(KMT5B):c.833A>T (p.Asn278Ile)	KMT5B	Pathogenic	no assertion criteria provided
1164063	NM_017635.5(KMT5B):c.541C>G (p.His181Asp)	KMT5B	Pathogenic	no assertion criteria provided
1203846	NM_017635.5(KMT5B):c.2422_2425del (p.Leu808fs)	KMT5B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326925	NM_017635.5(KMT5B):c.840+1_840+5del	KMT5B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679298	NM_017635.5(KMT5B):c.1530_1534del (p.His512fs)	KMT5B	Pathogenic	criteria provided, single submitter
1708391	NM_017635.5(KMT5B):c.1411G>T (p.Glu471Ter)	KMT5B	Pathogenic	criteria provided, single submitter
1895457	NM_017635.5(KMT5B):c.96dup (p.Gln33fs)	KMT5B	Pathogenic	criteria provided, single submitter
2575087	NM_017635.5(KMT5B):c.2347C>T (p.Arg783Ter)	KMT5B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2683928	NM_017635.5(KMT5B):c.1183C>T (p.Arg395Ter)	KMT5B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2687918	NM_017635.5(KMT5B):c.1823del (p.Gly608fs)	KMT5B	Pathogenic	criteria provided, single submitter
3377205	NM_017635.5(KMT5B):c.973G>T (p.Glu325Ter)	KMT5B	Pathogenic	criteria provided, single submitter
3377210	NM_017635.5(KMT5B):c.1298_1301del (p.Asn433fs)	KMT5B	Pathogenic	criteria provided, single submitter
3764547	NM_017635.5(KMT5B):c.913del (p.Cys305fs)	KMT5B	Pathogenic	criteria provided, single submitter
446521	NM_017635.5(KMT5B):c.725del (p.Leu242fs)	KMT5B	Pathogenic	criteria provided, multiple submitters, no conflicts
446522	NM_017635.5(KMT5B):c.1557_1558del (p.Asn520fs)	KMT5B	Pathogenic	no assertion criteria provided
4532162	NM_017635.5(KMT5B):c.1208del (p.Lys403fs)	KMT5B	Pathogenic	criteria provided, single submitter
4685484	NM_017635.5(KMT5B):c.609C>G (p.Tyr203Ter)	KMT5B	Pathogenic	criteria provided, single submitter
4685486	NM_017635.5(KMT5B):c.1727del (p.Gly576fs)	KMT5B	Pathogenic	criteria provided, single submitter
559640	NM_017635.5(KMT5B):c.255del (p.Ser86fs)	KMT5B	Pathogenic	no assertion criteria provided
560605	NM_017635.5(KMT5B):c.219del (p.Ala74fs)	KMT5B	Pathogenic	no assertion criteria provided
560606	NM_017635.5(KMT5B):c.559C>T (p.Arg187Ter)	KMT5B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
666575	NM_017635.5(KMT5B):c.856C>T (p.Arg286Ter)	KMT5B	Pathogenic	criteria provided, multiple submitters, no conflicts
802695	NM_017635.5(KMT5B):c.668_672del (p.Lys223fs)	KMT5B	Pathogenic	criteria provided, multiple submitters, no conflicts
976356	NM_017635.5(KMT5B):c.329C>G (p.Ser110Ter)	KMT5B	Pathogenic	criteria provided, single submitter
1334001	NM_017635.5(KMT5B):c.787C>T (p.Leu263Phe)	KMT5B	Likely pathogenic	criteria provided, single submitter
1801371	NM_017635.5(KMT5B):c.972C>G (p.Cys324Trp)	KMT5B	Likely pathogenic	criteria provided, single submitter
1805780	NM_017635.5(KMT5B):c.904G>A (p.Glu302Lys)	KMT5B	Likely pathogenic	criteria provided, single submitter
1809711	NM_017635.5(KMT5B):c.712GAG[1] (p.Glu239del)	KMT5B	Likely pathogenic	no assertion criteria provided
2499599	NM_017635.5(KMT5B):c.914G>A (p.Cys305Tyr)	KMT5B	Likely pathogenic	criteria provided, single submitter
3235070	NM_017635.5(KMT5B):c.634dup (p.Ile212fs)	KMT5B	Likely pathogenic	criteria provided, single submitter

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
KMT5B	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 51	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KMT5B	Orphanet:684226	Intellectual disability-hypotonia-facial dysmorphism-macrocephaly 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
KMT5B	HGNC:24283	ENSG00000110066	Q4FZB7	Histone-lysine N-methyltransferase KMT5B	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KMT5B	Histone-lysine N-methyltransferase KMT5B	Histone methyltransferase that specifically methylates monomethylated ‘Lys-20’ (H4K20me1) and dimethylated ‘Lys-20’ (H4K20me2) of histone H4 to produce respectively dimethylated ‘Lys-20’ (H4K20me2) and trimethylated ‘Lys-20’ (H4K20me3) and…

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)
KMT5B	Other/Unknown	no		SET_dom, Suv4-20_animal, Suv4-20/Set9

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
mucosa of paranasal sinus	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KMT5B	290	ubiquitous	marker	cortical plate, mucosa of paranasal sinus, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KMT5B	1,384

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KMT5B	Q4FZB7	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
PKMTs methylate histone lysines	1	160.8×	0.014	KMT5B
Chromatin organization	1	81.6×	0.014	KMT5B
Chromatin modifying enzymes	1	72.3×	0.014	KMT5B

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
positive regulation of isotype switching	1	1296.3×	0.003	KMT5B
positive regulation of double-strand break repair via nonhomologous end joining	1	991.3×	0.003	KMT5B
methylation	1	170.2×	0.007	KMT5B
muscle organ development	1	166.8×	0.007	KMT5B
DNA repair	1	63.8×	0.016	KMT5B

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
KMT5B	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
KMT5B	72	Binding:72

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	KMT5B

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)
KMT5B	72	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.