SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth

Summary

SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth (MONDO:0800477) is a disease caused by SETD2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SETD2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth
Mondo ID	MONDO:0800477
Is cancer (heuristic)	no

Also known as: SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth

Data availability: 1 ClinVar variant · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth

Related subtypes (9): syndromic intellectual disability, non-syndromic intellectual disability, intellectual developmental disorder and retinitis pigmentosa; IDDRP, PPP2R1A-related intellectual disability, intellectual disability, autosomal dominant, X-linked intellectual disability, intellectual disability, autosomal recessive, NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability, intellectual developmental disorder with polymicrogyria and seizures

Subtypes (2): SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome, intellectual developmental disorder, autosomal dominant 70

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

1 retrieved; paginated sample, class counts are floors:

1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
859857	NM_014159.7(SETD2):c.68C>G (p.Pro23Arg)	LOC129936665	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
SETD2	Strong	Autosomal dominant	SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SETD2	Orphanet:597738	Luscan-Lumish syndrome
SETD2	Orphanet:597743	SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies 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
SETD2	HGNC:18420	ENSG00000181555	Q9BYW2	Histone-lysine N-methyltransferase SETD2	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SETD2	Histone-lysine N-methyltransferase SETD2	Histone methyltransferase that specifically trimethylates ‘Lys-36’ of histone H3 (H3K36me3) using dimethylated ‘Lys-36’ (H3K36me2) as substrate.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SETD2	Scaffold/PPI	no	2.1.1.359	WW_dom, SET_dom, Post-SET_dom

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
colonic epithelium	1
endothelial cell	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SETD2	291	ubiquitous	marker	tendon of biceps brachii, endothelial cell, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SETD2	4,668

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SETD2	Q9BYW2	43

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	SETD2
Chromatin organization	1	81.6×	0.014	SETD2
Chromatin modifying enzymes	1	72.3×	0.014	SETD2

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
regulation of protein localization to chromatin	1	5617.3×	0.002	SETD2
microtubule cytoskeleton organization involved in mitosis	1	4213.0×	0.002	SETD2
peptidyl-lysine trimethylation	1	2808.7×	0.002	SETD2
nucleosome organization	1	2808.7×	0.002	SETD2
regulation of mRNA export from nucleus	1	2106.5×	0.002	SETD2
response to type I interferon	1	1872.4×	0.002	SETD2
response to metal ion	1	1532.0×	0.002	SETD2
response to alkaloid	1	1532.0×	0.002	SETD2
regulation of double-strand break repair via homologous recombination	1	991.3×	0.002	SETD2
positive regulation of ossification	1	936.2×	0.002	SETD2
mismatch repair	1	648.1×	0.003	SETD2
positive regulation of interferon-alpha production	1	648.1×	0.003	SETD2
endodermal cell differentiation	1	495.6×	0.003	SETD2
transcription elongation by RNA polymerase II	1	443.5×	0.003	SETD2
regulation of cytokinesis	1	421.3×	0.003	SETD2
stem cell differentiation	1	300.9×	0.004	SETD2
positive regulation of autophagy	1	208.1×	0.006	SETD2
regulation of gene expression	1	83.4×	0.013	SETD2
defense response to virus	1	69.3×	0.015	SETD2
regulation of DNA-templated transcription	1	31.6×	0.032	SETD2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 0

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
SETD2	3	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SINEFUNGIN	2	SETD2
MOLIBRESIB	2	SETD2
EZM-0414	1	SETD2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SETD2	64	Binding:64

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SETD2	2.1.1.359	[histone H3]-lysine36 N-trimethyltransferase

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

3 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)
SINEFUNGIN	2	SETD2
MOLIBRESIB	2	SETD2
EZM-0414	1	SETD2

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	1	SETD2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.