Intellectual developmental disorder with autism and macrocephaly

disease

On this page

Also known as autism, susceptibility to, 18autism, susceptibility to, type 18AUTS18CHD8 overgrowth syndromesusceptibility to autism 18

Summary

Intellectual developmental disorder with autism and macrocephaly (MONDO:0014017) is a disease caused by CHD8 (GenCC Strong), with 2 cohort genes.

At a glance

Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
Causal gene: CHD8 (GenCC Strong)
Cohort genes: 2
ClinVar variants: 234

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		73	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder with autism and macrocephaly
Mondo ID	MONDO:0014017
OMIM	615032
Orphanet	642675
UMLS	C3554373
MedGen	767287
GARD	0024965
Is cancer (heuristic)	no

Also known as: autism, susceptibility to, 18 · autism, susceptibility to, type 18 · AUTS18 · CHD8 overgrowth syndrome · susceptibility to autism 18

Data availability: 234 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease susceptibility › inherited disease susceptibility › autism, susceptiblity to › intellectual developmental disorder with autism and macrocephaly

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

234 retrieved; paginated sample, class counts are floors:

94 uncertain significance, 55 pathogenic, 40 likely pathogenic, 28 conflicting classifications of pathogenicity, 9 pathogenic/likely pathogenic, 5 likely benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033349	NM_001170629.2(CHD8):c.4744C>T (p.Arg1582Ter)	CHD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1064594	NM_001170629.2(CHD8):c.3308-1G>C	CHD8	Pathogenic	criteria provided, single submitter
1220256	NM_001170629.2(CHD8):c.4204C>T (p.Arg1402Ter)	CHD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1297051	NM_001170629.2(CHD8):c.5646_5647del (p.Arg1882fs)	CHD8	Pathogenic	criteria provided, single submitter
1328373	NM_001170629.2(CHD8):c.4875G>A (p.Trp1625Ter)	CHD8	Pathogenic	criteria provided, single submitter
1685628	NM_001170629.2(CHD8):c.6002del (p.Pro2001fs)	CHD8	Pathogenic	criteria provided, single submitter
1685629	NM_001170629.2(CHD8):c.4440G>T (p.Glu1480Asp)	CHD8	Pathogenic	criteria provided, single submitter
1687035	NM_001170629.2(CHD8):c.2065G>T (p.Glu689Ter)	CHD8	Pathogenic	no assertion criteria provided
1687036	NM_001170629.2(CHD8):c.4818-1G>A	CHD8	Pathogenic	no assertion criteria provided
1687037	NM_001170629.2(CHD8):c.3502T>A (p.Tyr1168Asn)	CHD8	Pathogenic	no assertion criteria provided
1694715	NM_001170629.2(CHD8):c.2726C>G (p.Ser909Ter)	CHD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699389	NM_001170629.2(CHD8):c.3308-2A>G	CHD8	Pathogenic	criteria provided, single submitter
1699404	NM_001170629.2(CHD8):c.5744del (p.Pro1915fs)	CHD8	Pathogenic	criteria provided, single submitter
1699441	NM_001170629.2(CHD8):c.3790_3796del (p.Glu1264fs)	CHD8	Pathogenic	criteria provided, single submitter
1708479	NM_001170629.2(CHD8):c.6527G>A (p.Trp2176Ter)	CHD8	Pathogenic	criteria provided, single submitter
1709073	NM_001170629.2(CHD8):c.1473_1477delinsAGGAA (p.Ser491_Val492delinsArgGly)	CHD8	Pathogenic	criteria provided, single submitter
1800961	NM_001170629.2(CHD8):c.4384C>T (p.Arg1462Ter)	CHD8	Pathogenic	criteria provided, multiple submitters, no conflicts
1802536	NM_001170629.2(CHD8):c.2025-1G>C	CHD8	Pathogenic	criteria provided, single submitter
1805207	NM_001170629.2(CHD8):c.2199_2200del (p.His734fs)	CHD8	Pathogenic	criteria provided, single submitter
216903	NM_001170629.2(CHD8):c.1744C>T (p.Arg582Ter)	CHD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2439084	NM_001170629.2(CHD8):c.5017C>T (p.Arg1673Ter)	CHD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2574671	NM_001170629.2(CHD8):c.3623G>T (p.Cys1208Phe)	CHD8	Pathogenic	no assertion criteria provided
2692590	NM_001170629.2(CHD8):c.949C>T (p.Gln317Ter)	CHD8	Pathogenic	criteria provided, single submitter
2920694	NM_001170629.2(CHD8):c.1228C>T (p.Gln410Ter)	CHD8	Pathogenic	criteria provided, single submitter
3065999	NM_001170629.2(CHD8):c.3996_3997del (p.Gln1332fs)	CHD8	Pathogenic	no assertion criteria provided
3236120	NM_001170629.2(CHD8):c.991C>T (p.Gln331Ter)	CHD8	Pathogenic	criteria provided, single submitter
3254731	NM_001170629.2(CHD8):c.5422C>T (p.Arg1808Ter)	CHD8	Pathogenic	criteria provided, multiple submitters, no conflicts
3256790	NM_001170629.2(CHD8):c.7054C>T (p.Arg2352Ter)	CHD8	Pathogenic	criteria provided, single submitter
3376320	NM_001170629.2(CHD8):c.6447_6450del (p.Arg2150fs)	CHD8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374261	NM_001170629.2(CHD8):c.6518C>A (p.Ser2173Ter)	CHD8	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
CHD8	Strong	Autosomal dominant	intellectual disability	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHD8	Orphanet:261229	14q11.2 microduplication syndrome
CHD8	Orphanet:642675	CHD8 overgrowth 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
CHD8	HGNC:20153	ENSG00000100888	Q9HCK8	ATP-dependent chromatin remodeler CHD8	gencc,clinvar
OR10G3	HGNC:8171	ENSG00000169208	Q8NGC4	Olfactory receptor 10G3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CHD8	ATP-dependent chromatin remodeler CHD8	ATP-dependent chromatin-remodeling factor, it slides nucleosomes along DNA; nucleosome sliding requires ATP.
OR10G3	Olfactory receptor 10G3	Odorant receptor.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
GPCR	1	12.0×	0.164
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHD8	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
OR10G3	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM

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
sural nerve	2
cortical plate	1
ventricular zone	1
male germ line stem cell (sensu Vertebrata) in testis	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHD8	283	ubiquitous	marker	sural nerve, ventricular zone, cortical plate
OR10G3	114		marker	male germ line stem cell (sensu Vertebrata) in testis, right lung, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHD8	4,791
OR10G3	280

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHD8	Q9HCK8	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OR10G3	Q8NGC4	87.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Deactivation of the beta-catenin transactivating complex	1	116.5×	0.018	CHD8
CHD6, CHD7, CHD8, CHD9 subfamily	1	74.2×	0.018	CHD8
Olfactory Signaling Pathway	1	72.3×	0.018	OR10G3
Expression and translocation of olfactory receptors	1	14.1×	0.070	OR10G3

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of fibroblast apoptotic process	1	1203.7×	0.011	CHD8
prepulse inhibition	1	561.7×	0.011	CHD8
positive regulation of transcription by RNA polymerase III	1	468.1×	0.011	CHD8
digestive tract development	1	263.3×	0.015	CHD8
social behavior	1	135.9×	0.024	CHD8
detection of chemical stimulus involved in sensory perception of smell	1	62.0×	0.037	OR10G3
negative regulation of canonical Wnt signaling pathway	1	58.9×	0.037	CHD8
Wnt signaling pathway	1	49.9×	0.037	CHD8
brain development	1	39.8×	0.037	CHD8
mRNA processing	1	39.4×	0.037	CHD8
chromatin remodeling	1	36.5×	0.037	CHD8
in utero embryonic development	1	36.0×	0.037	CHD8
negative regulation of DNA-templated transcription	1	15.8×	0.077	CHD8
positive regulation of DNA-templated transcription	1	14.0×	0.080	CHD8
negative regulation of transcription by RNA polymerase II	1	8.9×	0.117	CHD8
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	CHD8

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CHD8	1	2
OR10G3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	CHD8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CHD8	7	Binding:7

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

1 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)
MOLIBRESIB	2	CHD8

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	CHD8
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	OR10G3
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)
OR10G3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: CHD8, OR10G3