Intellectual developmental disorder, autosomal dominant 65

Summary

Intellectual developmental disorder, autosomal dominant 65 (MONDO:0023657) is a disease caused by KDM4B (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: KDM4B (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 58

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder, autosomal dominant 65
Mondo ID	MONDO:0023657
OMIM	619320
DOID	DOID:0061038
UMLS	C5543371
MedGen	1787923
GARD	0018547
Is cancer (heuristic)	no

Also known as: mental retardation, autosomal dominant 65 · MRD65

Data availability: 58 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › intellectual disability, autosomal dominant › intellectual developmental disorder, autosomal dominant 65

Related subtypes (28): intellectual disability, autosomal dominant 1, intellectual disability, autosomal dominant 3, intellectual disability, autosomal dominant 4, intellectual disability, autosomal dominant 5, intellectual disability, autosomal dominant 6, intellectual disability, autosomal dominant 2, neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant, intellectual disability, autosomal dominant 9, intellectual disability, autosomal dominant 10, intellectual disability, autosomal dominant 11, intellectual disability, autosomal dominant 24, intellectual disability, autosomal dominant 38, intellectual disability, autosomal dominant 39, intellectual disability, autosomal dominant 40, intellectual disability, autosomal dominant 42, autosomal dominant non-syndromic intellectual disability, intellectual developmental disorder, autosomal dominant 69, intellectual developmental disorder, autosomal dominant 66, intellectual developmental disorder, autosomal dominant 64, intellectual developmental disorder, autosomal dominant 67, intellectual developmental disorder, autosomal dominant 68, autosomal dominant syndromic intellectual disability, intellectual developmental disorder, autosomal dominant 70, intellectual developmental disorder, autosomal dominant 71, with behavioral abnormalities, intellectual developmental disorder, autosomal dominant 72, intellectual developmental disorder, autosomal dominant 74, intellectual developmental disorder, autosomal dominant 75, intellectual developmental disorder, autosomal dominant 76

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

58 retrieved; paginated sample, class counts are floors:

32 uncertain significance, 19 likely pathogenic, 4 pathogenic, 2 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1098738	NM_015015.3(KDM4B):c.659T>C (p.Leu220Pro)	KDM4B	Pathogenic	no assertion criteria provided
1098739	NM_015015.3(KDM4B):c.2221dup (p.Glu741fs)	KDM4B	Pathogenic	no assertion criteria provided
1098740	NM_015015.3(KDM4B):c.1778_1779del (p.Glu593fs)	KDM4B	Pathogenic	no assertion criteria provided
1802611	NM_015015.3(KDM4B):c.1783C>T (p.Gln595Ter)	KDM4B	Pathogenic	criteria provided, single submitter
1329940	NM_015015.3(KDM4B):c.2441+1G>A	KDM4B	Likely pathogenic	criteria provided, single submitter
1679582	NM_015015.3(KDM4B):c.2440_2441+1del	KDM4B	Likely pathogenic	criteria provided, single submitter
1804113	NM_015015.3(KDM4B):c.1198_1222del (p.Ala399_Leu400insTer)	KDM4B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1992399	NM_015015.3(KDM4B):c.2935G>T (p.Glu979Ter)	KDM4B	Likely pathogenic	criteria provided, single submitter
2428732	NM_015015.3(KDM4B):c.2661_2677del (p.Val888fs)	KDM4B	Likely pathogenic	criteria provided, single submitter
2429016	NM_015015.3(KDM4B):c.2343dup (p.Gly782fs)	KDM4B	Likely pathogenic	criteria provided, single submitter
2576583	NM_015015.3(KDM4B):c.1316-1G>A	KDM4B	Likely pathogenic	criteria provided, single submitter
2664875	NM_015015.3(KDM4B):c.2550+2T>C	KDM4B	Likely pathogenic	criteria provided, single submitter
3062355	NM_015015.3(KDM4B):c.994_998del (p.Leu332fs)	KDM4B	Likely pathogenic	criteria provided, single submitter
3068476	NM_015015.3(KDM4B):c.1217del (p.Gly406fs)	KDM4B	Likely pathogenic	criteria provided, single submitter
3777114	NM_015015.3(KDM4B):c.2085+2del	KDM4B	Likely pathogenic	criteria provided, single submitter
3779785	NM_015015.3(KDM4B):c.2901+59_2901+60insTCCCGAGAGCATCACGGTGAGCTGTGGGGTGGGGCAGGGGGCGGGGGGAGGCTGGGAGCACAGCGACAACCTGTA	KDM4B	Likely pathogenic	criteria provided, single submitter
4056537	NM_015015.3(KDM4B):c.2329G>T (p.Glu777Ter)	KDM4B	Likely pathogenic	criteria provided, single submitter
4081468	NM_015015.3(KDM4B):c.2442-5_2445delinsGC	KDM4B	Likely pathogenic	criteria provided, single submitter
4293019	NM_015015.3(KDM4B):c.1980G>A (p.Trp660Ter)	KDM4B	Likely pathogenic	criteria provided, single submitter
4293073	NM_015015.3(KDM4B):c.1771del (p.Ala591fs)	KDM4B	Likely pathogenic	criteria provided, single submitter
4293687	NM_015015.3(KDM4B):c.253C>T (p.Gln85Ter)	KDM4B	Likely pathogenic	criteria provided, single submitter
4531250	NM_015015.3(KDM4B):c.2112del (p.Pro704_Ile705insTer)	KDM4B	Likely pathogenic	criteria provided, single submitter
983228	NM_015015.3(KDM4B):c.664C>T (p.Arg222Trp)	KDM4B	Likely pathogenic	criteria provided, single submitter
2649098	NM_015015.3(KDM4B):c.1401_1402insGGG (p.Pro467_Pro468insGly)	KDM4B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
983500	NM_015015.3(KDM4B):c.288C>T (p.Gly96=)	KDM4B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1343257	NM_015015.3(KDM4B):c.313G>A (p.Glu105Lys)	KDM4B	Uncertain significance	criteria provided, single submitter
1693289	NM_015015.3(KDM4B):c.2464A>G (p.Ile822Val)	KDM4B	Uncertain significance	criteria provided, single submitter
2262713	NM_015015.3(KDM4B):c.2117C>G (p.Ala706Gly)	KDM4B	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431518	NM_015015.3(KDM4B):c.2878A>G (p.Asn960Asp)	KDM4B	Uncertain significance	criteria provided, single submitter
2431784	NM_015015.3(KDM4B):c.167C>T (p.Pro56Leu)	KDM4B	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
KDM4B	Strong	Autosomal dominant	intellectual developmental disorder, autosomal dominant 65	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KDM4B	Orphanet:528084	Non-specific syndromic intellectual disability
OCRL	Orphanet:534	Oculocerebrorenal syndrome of Lowe
OCRL	Orphanet:93623	Dent disease type 2

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
KDM4B	HGNC:29136	ENSG00000127663	O94953	Lysine-specific demethylase 4B	gencc,clinvar
OCRL	HGNC:8108	ENSG00000122126	Q01968	Inositol polyphosphate 5-phosphatase OCRL	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KDM4B	Lysine-specific demethylase 4B	Histone demethylase that specifically demethylates ‘Lys-9’ of histone H3, thereby playing a role in histone code.
OCRL	Inositol polyphosphate 5-phosphatase OCRL	Catalyzes the hydrolysis of the 5-position phosphate of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol-3,4,5-bisphosphate (PtdIns(3,4,5)P3), with the greatest catalytic activity towards PtdIns(4,5)P2.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Antibody/Immunoglobulin	1	14.6×	0.135
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KDM4B	Transcription factor	no	1.14.11.27	Znf_PHD, Tudor, JmjC_dom
OCRL	Antibody/Immunoglobulin	yes	3.1.3.36	RhoGAP_dom, IPPc, Rho_GTPase_activation_prot

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
cervix squamous epithelium	1
corpus epididymis	1
dorsal motor nucleus of vagus nerve	1
Brodmann (1909) area 10	1
endometrium epithelium	1
lower esophagus muscularis layer	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KDM4B	291	ubiquitous	marker	cervix squamous epithelium, dorsal motor nucleus of vagus nerve, corpus epididymis
OCRL	225	ubiquitous	marker	endometrium epithelium, Brodmann (1909) area 10, lower esophagus muscularis layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OCRL	2,269
KDM4B	1,533

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KDM4B	O94953	6
OCRL	Q01968	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. 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
Synthesis of IP2, IP, and Ins in the cytosol	1	380.7×	0.021	OCRL
Synthesis of PIPs at the Golgi membrane	1	317.2×	0.021	OCRL
DNA Double Strand Break Response	1	237.9×	0.021	KDM4B
Synthesis of IP3 and IP4 in the cytosol	1	211.5×	0.021	OCRL
DNA Double-Strand Break Repair	1	124.1×	0.021	KDM4B
HDMs demethylate histones	1	114.2×	0.021	KDM4B
Synthesis of PIPs at the plasma membrane	1	105.7×	0.021	OCRL
Golgi Associated Vesicle Biogenesis	1	100.2×	0.021	OCRL
RHOJ GTPase cycle	1	100.2×	0.021	OCRL
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	73.2×	0.026	KDM4B
ESR-mediated signaling	1	64.2×	0.027	KDM4B
RAC3 GTPase cycle	1	59.5×	0.027	OCRL
Signaling by Nuclear Receptors	1	51.0×	0.027	KDM4B
DNA Repair	1	49.2×	0.027	KDM4B
Clathrin-mediated endocytosis	1	42.6×	0.029	OCRL
Chromatin organization	1	40.8×	0.029	KDM4B
Estrogen-dependent gene expression	1	37.8×	0.029	KDM4B
Chromatin modifying enzymes	1	36.1×	0.029	KDM4B
Signal Transduction	1	5.1×	0.187	KDM4B

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
inositol phosphate metabolic process	1	495.6×	0.014	OCRL
phosphatidylinositol dephosphorylation	1	324.1×	0.014	OCRL
membrane organization	1	255.3×	0.014	OCRL
phosphatidylinositol biosynthetic process	1	183.2×	0.015	OCRL
lipid metabolic process	1	45.8×	0.030	OCRL
regulation of gene expression	1	41.7×	0.030	KDM4B
brain development	1	39.8×	0.030	KDM4B
cilium assembly	1	36.8×	0.030	OCRL
chromatin remodeling	1	36.5×	0.030	KDM4B
in utero embryonic development	1	36.0×	0.030	OCRL
signal transduction	1	8.0×	0.121	OCRL

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
KDM4B	CICLOPIROX

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KDM4B	5	4
OCRL	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CICLOPIROX	4	KDM4B
TANESPIMYCIN	3	KDM4B
GELDANAMYCIN	2	KDM4B
ALVESPIMYCIN	2	KDM4B
ZAVONDEMSTAT	2	KDM4B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
KDM4B	61	Binding:60, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KDM4B	1.14.11.27, 1.14.11.66, 1.14.11.69	[histone H3]-dimethyl-L-lysine36 demethylase, [histone H3]-trimethyl-L-lysine9 demethylase, [histone H3]-trimethyl-L-lysine36 demethylase
OCRL	3.1.3.36	phosphoinositide 5-phosphatase

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

5 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)
CICLOPIROX	4	KDM4B
TANESPIMYCIN	3	KDM4B
GELDANAMYCIN	2	KDM4B
ALVESPIMYCIN	2	KDM4B
ZAVONDEMSTAT	2	KDM4B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KDM4B
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	OCRL
D	Druggable family + AlphaFold only, no drug	0
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)
OCRL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.