Intellectual disability, autosomal dominant 22

Summary

Intellectual disability, autosomal dominant 22 (MONDO:0012869) is a disease caused by ZBTB18 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: ZBTB18 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 89

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 22
Mondo ID	MONDO:0012869
MeSH	C567346
OMIM	612337
DOID	DOID:0070052
GARD	0024892
Is cancer (heuristic)	no

Also known as: autosomal dominant intellectual disability 22 · autosomal dominant non-syndromic intellectual disability caused by mutation in ZBTB18 · intellectual disability, autosomal dominant 22 · intellectual disability, autosomal dominant type 22 · mental retardation, autosomal dominant 22 · mental retardation, autosomal dominant type 22 · MRD22 · ZBTB18 autosomal dominant non-syndromic intellectual disability

Data availability: 89 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 22

Related subtypes (25): 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 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

89 retrieved; paginated sample, class counts are floors:

28 pathogenic, 23 likely pathogenic, 19 uncertain significance, 9 conflicting classifications of pathogenicity, 4 pathogenic/likely pathogenic, 4 likely benign, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703535	GRCh37/hg19 1q43-44(chr1:242816510-244797117)	ADSS2	Pathogenic	no assertion criteria provided
2579272	GRCh38/hg38 1q43-44(chr1:243221458-248919110)x1	ADSS2	Pathogenic	criteria provided, single submitter
2579277	GRCh38/hg38 1q43-44(chr1:242164274-245299473)x1	ADSS2	Pathogenic	criteria provided, single submitter
2582785	GRCh38/hg38 1q43-44(chr1:239907336-248919110)x1	ADSS2	Pathogenic	criteria provided, single submitter
2582786	GRCh38/hg38 1q43-44(chr1:242520315-246857912)x1	ADSS2	Pathogenic	criteria provided, single submitter
2579286	GRCh38/hg38 1q42.3-44(chr1:235215476-247005888)x1	LOC129388792	Pathogenic	criteria provided, single submitter
1032618	NM_205768.3(ZBTB18):c.1378C>T (p.His460Tyr)	ZBTB18	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066831	NM_205768.3(ZBTB18):c.1406A>G (p.His469Arg)	ZBTB18	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1319911	NM_205768.3(ZBTB18):c.550del (p.Asp184fs)	ZBTB18	Pathogenic	no assertion criteria provided
1333608	NM_205768.3(ZBTB18):c.579G>A (p.Trp193Ter)	ZBTB18	Pathogenic	criteria provided, single submitter
1801353	NM_205768.3(ZBTB18):c.1142_1146delinsAACCCT (p.Cys381_Pro382delinsTer)	ZBTB18	Pathogenic	criteria provided, single submitter
1802618	NM_205768.3(ZBTB18):c.691_692del (p.Leu231fs)	ZBTB18	Pathogenic	criteria provided, single submitter
208690	NM_205768.3(ZBTB18):c.1382A>G (p.Asn461Ser)	ZBTB18	Pathogenic	criteria provided, multiple submitters, no conflicts
225892	NM_205768.3(ZBTB18):c.1183C>T (p.Gln395Ter)	ZBTB18	Pathogenic	criteria provided, multiple submitters, no conflicts
225922	NM_205768.3(ZBTB18):c.943_944del (p.Arg315fs)	ZBTB18	Pathogenic	criteria provided, multiple submitters, no conflicts
225923	NM_205768.3(ZBTB18):c.133C>T (p.Arg45Ter)	ZBTB18	Pathogenic	criteria provided, multiple submitters, no conflicts
2579278	GRCh38/hg38 1q44(chr1:244051186-244055631)x1	ZBTB18	Pathogenic	criteria provided, single submitter
3254938	NM_205768.3(ZBTB18):c.562G>T (p.Glu188Ter)	ZBTB18	Pathogenic	criteria provided, single submitter
397517	NM_205768.3(ZBTB18):c.599del (p.Asp199_Ser200insTer)	ZBTB18	Pathogenic	criteria provided, single submitter
417741	NM_205768.3(ZBTB18):c.583C>T (p.Arg195Ter)	ZBTB18	Pathogenic	criteria provided, single submitter
431091	NM_205768.3(ZBTB18):c.142C>T (p.Arg48Ter)	ZBTB18	Pathogenic	criteria provided, multiple submitters, no conflicts
440857	NM_205768.3(ZBTB18):c.1390C>T (p.Arg464Cys)	ZBTB18	Pathogenic	criteria provided, single submitter
4531409	NM_205768.3(ZBTB18):c.1354T>C (p.Cys452Arg)	ZBTB18	Pathogenic	criteria provided, single submitter
4538212	NM_205768.3(ZBTB18):c.942_943dup (p.Arg315fs)	ZBTB18	Pathogenic	criteria provided, single submitter
4813789	NM_205768.3(ZBTB18):c.1322_1325del (p.His441fs)	ZBTB18	Pathogenic	criteria provided, single submitter
4819202	Single allele	ZBTB18	Pathogenic	criteria provided, single submitter
617452	NM_205768.3(ZBTB18):c.1391G>A (p.Arg464His)	ZBTB18	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
801642	NM_205768.3(ZBTB18):c.967_968insG (p.Leu323fs)	ZBTB18	Pathogenic	criteria provided, single submitter
88856	NM_205768.3(ZBTB18):c.397G>T (p.Glu133Ter)	ZBTB18	Pathogenic	no assertion criteria provided
975780	NM_205768.3(ZBTB18):c.1143C>A (p.Cys381Ter)	ZBTB18	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ZBTB18	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 22	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZBTB18	Orphanet:36367	Distal deletion 1q syndrome

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
ZBTB18	HGNC:13030	ENSG00000179456	Q99592	Zinc finger and BTB domain-containing protein 18	gencc,clinvar
ADSS2	HGNC:292	ENSG00000035687	P30520	Adenylosuccinate synthetase isozyme 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZBTB18	Zinc finger and BTB domain-containing protein 18	Transcriptional repressor that plays a role in various developmental processes such as myogenesis and brain development.
ADSS2	Adenylosuccinate synthetase isozyme 2	Plays an important role in the de novo pathway and in the salvage pathway of purine nucleotide biosynthesis.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZBTB18	Transcription factor	no		BTB/POZ_dom, SKP1/BTB/POZ_sf, Znf_C2H2_type
ADSS2	Other/Unknown	no		Adenylosuccinate_synthetase, Adenylosuccin_syn_GTP-bd, P-loop_NTPase

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
cerebellar vermis	1
cortical plate	1
paraflocculus	1
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZBTB18	292	ubiquitous	marker	cerebellar vermis, paraflocculus, cortical plate
ADSS2	285	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADSS2	2,681
ZBTB18	1,520

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZBTB18	Q99592	1
ADSS2	P30520	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Purine ribonucleoside monophosphate biosynthesis	1	1038.2×	1e-03	ADSS2

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
response to ammonium ion	1	8426.0×	0.002	ADSS2
AMP biosynthetic process	1	2106.5×	0.002	ADSS2
IMP metabolic process	1	2106.5×	0.002	ADSS2
aspartate metabolic process	1	1053.2×	0.002	ADSS2
response to purine-containing compound	1	1053.2×	0.002	ADSS2
‘de novo’ AMP biosynthetic process	1	1053.2×	0.002	ADSS2
cellular response to electrical stimulus	1	648.1×	0.003	ADSS2
immune system process	1	195.9×	0.008	ADSS2
skeletal muscle tissue development	1	145.3×	0.010	ZBTB18
negative regulation of DNA-templated transcription	1	15.8×	0.081	ZBTB18
negative regulation of transcription by RNA polymerase II	1	8.9×	0.130	ZBTB18
positive regulation of transcription by RNA polymerase II	1	7.4×	0.141	ZBTB18
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ZBTB18

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ZBTB18	0	0
ADSS2	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
ADSS2	2	Binding:2

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

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	2	ZBTB18, ADSS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZBTB18	0	—
ADSS2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.