Intellectual disability, autosomal dominant 45

Summary

Intellectual disability, autosomal dominant 45 (MONDO:0030910) is a disease caused by CIC (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: CIC (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 166

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 45
Mondo ID	MONDO:0030910
OMIM	617600
DOID	DOID:0080236
UMLS	C4539848
MedGen	1616472
GARD	0025658
Is cancer (heuristic)	no

Also known as: autosomal dominant mental retardation 45 · intellectual disability, autosomal dominant 45 · mental retardation, autosomal dominant 45 · MRD45

Data availability: 166 ClinVar variants · 3 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 45

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 46, intellectual disability, autosomal dominant 47, Clark-Baraitser syndrome, intellectual disability, autosomal dominant 50, intellectual disability, autosomal dominant 51, 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

166 retrieved; paginated sample, class counts are floors:

98 uncertain significance, 27 likely pathogenic, 17 conflicting classifications of pathogenicity, 15 pathogenic, 6 likely benign, 2 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030471	NM_001386298.1(CIC):c.3400C>T (p.Gln1134Ter)	CIC	Pathogenic	criteria provided, multiple submitters, no conflicts
1064629	NM_001386298.1(CIC):c.3179+1G>T	CIC	Pathogenic	criteria provided, multiple submitters, no conflicts
1301398	NM_001386298.1(CIC):c.1100dup (p.Pro368fs)	CIC	Pathogenic	criteria provided, single submitter
1301400	NM_001386298.1(CIC):c.6166_6167del (p.Ala2056fs)	CIC	Pathogenic	criteria provided, single submitter
1805941	NM_001386298.1(CIC):c.6074dup (p.Ser2026fs)	CIC	Pathogenic	criteria provided, single submitter
3063953	NC_000019.9:g.(?42785739)(42791254_?)del	CIC	Pathogenic	criteria provided, single submitter
3068400	NM_001386298.1(CIC):c.2363del (p.Pro788fs)	CIC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3075672	NM_001386298.1(CIC):c.1027del (p.Trp343fs)	CIC	Pathogenic	criteria provided, single submitter
3234056	NM_001386298.1(CIC):c.2322_2323del (p.Arg775fs)	CIC	Pathogenic	criteria provided, single submitter
4279548	NM_001386298.1(CIC):c.6367C>T (p.Arg2123Ter)	CIC	Pathogenic	criteria provided, single submitter
431168	NM_001386298.1(CIC):c.3784C>T (p.Arg1262Ter)	CIC	Pathogenic	criteria provided, single submitter
431169	NM_001386298.1(CIC):c.4528_4535dup (p.Glu1513fs)	CIC	Pathogenic	no assertion criteria provided
431170	NM_001386298.1(CIC):c.5298_5313del (p.Pro1767fs)	CIC	Pathogenic	no assertion criteria provided
437890	NM_001386298.1(CIC):c.4201C>T (p.Arg1401Trp)	CIC	Pathogenic	no assertion criteria provided
4845401	NM_001386298.1(CIC):c.4169_4170insT (p.Glu1391fs)	CIC	Pathogenic	criteria provided, single submitter
637047	NM_001386298.1(CIC):c.3163_3164del (p.Glu1054_Ser1055insTer)	CIC	Pathogenic	criteria provided, single submitter
127106	NM_001080517.3(SETD5):c.3856del (p.Ser1286fs)	SETD5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334748	NM_001386298.1(CIC):c.1582C>T (p.Arg528Ter)	CIC	Likely pathogenic	criteria provided, single submitter
1338808	NM_001386298.1(CIC):c.6793G>T (p.Glu2265Ter)	CIC	Likely pathogenic	criteria provided, single submitter
1676528	NM_001386298.1(CIC):c.6344del (p.Gln2115fs)	CIC	Likely pathogenic	criteria provided, single submitter
1709980	NM_001386298.1(CIC):c.1026dup (p.Trp343fs)	CIC	Likely pathogenic	criteria provided, single submitter
1723880	NM_001386298.1(CIC):c.5424del (p.Ala1809fs)	CIC	Likely pathogenic	criteria provided, single submitter
1805467	NM_001386298.1(CIC):c.111_112del (p.Asp38fs)	CIC	Likely pathogenic	criteria provided, single submitter
2581048	NM_001386298.1(CIC):c.3428T>C (p.Leu1143Pro)	CIC	Likely pathogenic	criteria provided, single submitter
2633551	NM_001386298.1(CIC):c.5903-2A>G	CIC	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2664935	NM_001386298.1(CIC):c.6055C>T (p.Gln2019Ter)	CIC	Likely pathogenic	criteria provided, single submitter
3027449	NM_001386298.1(CIC):c.1631del (p.Gly544fs)	CIC	Likely pathogenic	criteria provided, single submitter
3066278	NM_001386298.1(CIC):c.4869del (p.Ser1624fs)	CIC	Likely pathogenic	criteria provided, single submitter
3358946	NM_001386298.1(CIC):c.5903-1G>A	CIC	Likely pathogenic	criteria provided, single submitter
3897832	NM_001386298.1(CIC):c.2680_2692del (p.Gln894fs)	CIC	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 5 · 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
CIC	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 45	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CIC	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
BCL11A	Orphanet:251380	Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
BCL11A	Orphanet:619233	Hereditary persistence of fetal hemoglobin-intellectual disability syndrome
SETD5	Orphanet:435638	3p25.3 microdeletion syndrome
SETD5	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CIC	HGNC:14214	ENSG00000079432	Q96RK0	Protein capicua homolog	gencc,clinvar
BCL11A	HGNC:13221	ENSG00000119866	Q9H165	BCL11 transcription factor A	clinvar
SETD5	HGNC:25566	ENSG00000168137	Q9C0A6	Histone-lysine N-methyltransferase SETD5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CIC	Protein capicua homolog	Transcriptional repressor which plays a role in development of the central nervous system (CNS).
BCL11A	BCL11 transcription factor A	Transcription factor.
SETD5	Histone-lysine N-methyltransferase SETD5	Chromatin regulator required for brain development: acts as a regulator of RNA elongation rate, thereby regulating neural stem cell (NSC) proliferation and synaptic transmission.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CIC	Other/Unknown	no		HMG_box_dom, Cic_dom, HMG_box_dom_sf
BCL11A	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Dev/Hematopoietic_TF
SETD5	Other/Unknown	no		SET_dom, SETD5_SET, SET_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
cortical plate	1
ganglionic eminence	1
primary visual cortex	1
adrenal tissue	1
colonic epithelium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CIC	274	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
BCL11A	247	ubiquitous	marker	cortical plate, ganglionic eminence, primary visual cortex
SETD5	284	ubiquitous	marker	adrenal tissue, colonic epithelium, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BCL11A	2,389
SETD5	1,865
CIC	1,720

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BCL11A	Q9H165	17
CIC	Q96RK0	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SETD5	Q9C0A6	47.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 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
ALK mutants bind TKIs	1	951.7×	0.005	BCL11A
Formation of the embryonic stem cell BAF (esBAF) complex	1	601.0×	0.005	BCL11A
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	456.8×	0.005	BCL11A
Signaling by ALK in cancer	1	271.9×	0.006	BCL11A
Signaling by ALK fusions and activated point mutants	1	150.3×	0.009	BCL11A
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.021	BCL11A
Disease	1	13.1×	0.076	BCL11A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of neuron remodeling	1	5617.3×	0.003	BCL11A
negative regulation of branching morphogenesis of a nerve	1	5617.3×	0.003	BCL11A
negative regulation of protein homooligomerization	1	1872.4×	0.006	BCL11A
negative regulation of dendrite extension	1	1404.3×	0.006	BCL11A
negative regulation of transcription by RNA polymerase III	1	1123.5×	0.006	SETD5
regulation of DNA-templated transcription elongation	1	936.2×	0.006	SETD5
negative regulation of dendrite development	1	702.2×	0.006	BCL11A
positive regulation of collateral sprouting	1	624.1×	0.006	BCL11A
cellular response to L-glutamate	1	561.7×	0.006	BCL11A
negative regulation of collateral sprouting	1	510.7×	0.006	BCL11A
regulation of chromatin organization	1	510.7×	0.006	SETD5
regulation of dendrite development	1	330.4×	0.008	BCL11A
negative regulation of axon extension	1	244.2×	0.009	BCL11A
regulation of synapse assembly	1	234.1×	0.009	SETD5
lung alveolus development	1	117.0×	0.017	CIC
protein sumoylation	1	108.0×	0.017	BCL11A
negative regulation of transcription by RNA polymerase II	2	11.8×	0.017	CIC, BCL11A
cognition	1	95.2×	0.017	SETD5
learning	1	93.6×	0.017	CIC
social behavior	1	90.6×	0.017	CIC
negative regulation of neuron projection development	1	79.1×	0.019	BCL11A
memory	1	61.1×	0.023	CIC
methylation	1	56.7×	0.024	SETD5
regulation of transcription by RNA polymerase II	2	7.8×	0.027	CIC, BCL11A
positive regulation of neuron projection development	1	45.7×	0.027	BCL11A
brain development	1	26.5×	0.044	CIC
transcription by RNA polymerase II	1	23.5×	0.048	CIC
positive regulation of gene expression	1	12.9×	0.084	BCL11A
regulation of DNA-templated transcription	1	10.5×	0.095	SETD5
negative regulation of DNA-templated transcription	1	10.5×	0.095	CIC

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CIC	0	0
BCL11A	0	0
SETD5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	CIC, BCL11A, SETD5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CIC	0	—
BCL11A	0	—
SETD5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.