Kleefstra syndrome due to a point mutation

Summary

Kleefstra syndrome due to a point mutation (MONDO:0016865) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 50

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		23	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0000078	Abnormality of the genital system	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001548	Overgrowth	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0002719	Recurrent infections	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000076	Vesicoureteral reflux	Occasional (5-29%)
HP:0000077	Abnormality of the kidney	Occasional (5-29%)
HP:0000179	Thick lower lip vermilion	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001321	Cerebellar hypoplasia	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001520	Large for gestational age	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002194	Delayed gross motor development	Occasional (5-29%)
HP:0002463	Language impairment	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0006863	Severe expressive language delay	Occasional (5-29%)
HP:0009909	Uplifted earlobe	Occasional (5-29%)
HP:0011351	Moderate receptive language delay	Occasional (5-29%)
HP:0011800	Midface retrusion	Occasional (5-29%)
HP:0033127	Abnormality of the musculoskeletal system	Occasional (5-29%)
HP:0100716	Self-injurious behavior	Occasional (5-29%)
HP:0200005	Abnormal shape of the palpebral fissure	Occasional (5-29%)
HP:0000164	Abnormality of the dentition	Very rare (<1-4%)
HP:0000248	Brachycephaly	Very rare (<1-4%)
HP:0000519	Developmental cataract	Very rare (<1-4%)
HP:0000540	Hypermetropia	Very rare (<1-4%)
HP:0000695	Natal tooth	Very rare (<1-4%)
HP:0000826	Precocious puberty	Very rare (<1-4%)
HP:0000974	Hyperextensible skin	Very rare (<1-4%)
HP:0001182	Tapered finger	Very rare (<1-4%)
HP:0001252	Hypotonia	Very rare (<1-4%)
HP:0001357	Plagiocephaly	Very rare (<1-4%)
HP:0001537	Umbilical hernia	Very rare (<1-4%)
HP:0002023	Anal atresia	Very rare (<1-4%)
HP:0002171	Gliosis	Very rare (<1-4%)
HP:0002779	Tracheomalacia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Kleefstra syndrome due to a point mutation
Mondo ID	MONDO:0016865
Orphanet	261652
UMLS	C5680724
MedGen	1826146
GARD	0017253
Is cancer (heuristic)	no

Data availability: 1 ClinVar variant.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › Kleefstra syndrome › Kleefstra syndrome due to a point mutation

Related subtypes (2): Kleefstra syndrome 1, Kleefstra syndrome 2

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 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
667417	NM_170606.3(KMT2C):c.3462del (p.Leu1155_Val1156insTer)	KMT2C	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KMT2C	Orphanet:261652	Kleefstra syndrome due to a point mutation

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
KMT2C	HGNC:13726	ENSG00000055609	Q8NEZ4	Histone-lysine N-methyltransferase 2C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KMT2C	Histone-lysine N-methyltransferase 2C	Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4).

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KMT2C	Transcription factor	no		HMGI/Y_DNA-bd_CS, SET_dom, Znf_RING

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
caput epididymis	1
oocyte	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KMT2C	261	ubiquitous	marker	oocyte, caput epididymis, upper arm skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KMT2C	3,321

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KMT2C	Q8NEZ4	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
Activation of HOX genes during differentiation	1	439.2×	0.018	KMT2C
Formation of WDR5-containing histone-modifying complexes	1	265.6×	0.018	KMT2C
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	215.5×	0.018	KMT2C
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	196.9×	0.018	KMT2C
PKMTs methylate histone lysines	1	160.8×	0.018	KMT2C
Epigenetic regulation by WDR5-containing histone modifying complexes	1	154.3×	0.018	KMT2C
Transcriptional regulation by RUNX1	1	146.4×	0.018	KMT2C
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	1	120.2×	0.018	KMT2C
Regulation of PD-L1(CD274) transcription	1	108.8×	0.018	KMT2C
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	91.4×	0.018	KMT2C
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	82.8×	0.018	KMT2C
Chromatin organization	1	81.6×	0.018	KMT2C
Chromatin modifying enzymes	1	72.3×	0.018	KMT2C
Epigenetic regulation of gene expression	1	71.4×	0.018	KMT2C
RNA Polymerase II Transcription	1	22.5×	0.053	KMT2C
Gene expression (Transcription)	1	17.8×	0.063	KMT2C
Generic Transcription Pathway	1	15.1×	0.069	KMT2C
Developmental Biology	1	14.5×	0.069	KMT2C

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
methylation	1	170.2×	0.012	KMT2C
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	KMT2C

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
KMT2C	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
KMT2C	29	Binding:29

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	KMT2C

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)
KMT2C	29	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.