Intellectual developmental disorder, autosomal dominant 63, with macrocephaly

Summary

Intellectual developmental disorder, autosomal dominant 63, with macrocephaly (MONDO:0032939) is a disease caused by TRIO (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: TRIO (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 93

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder, autosomal dominant 63, with macrocephaly
Mondo ID	MONDO:0032939
OMIM	618825
DOID	DOID:0061036
UMLS	C5394205
MedGen	1716581
GARD	0025781
Is cancer (heuristic)	no

Also known as: MRD63

Data availability: 93 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 developmental disorder, autosomal dominant 63, with macrocephaly

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 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, 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

93 retrieved; paginated sample, class counts are floors:

44 uncertain significance, 13 benign, 13 likely pathogenic, 8 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 5 benign/likely benign, 3 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2446724	GRCh37/hg19 5p15.2-15.1(chr5:10165922-18156739)x3	ANKH	Pathogenic	no assertion criteria provided
1709067	NM_007118.4(TRIO):c.7050del (p.Val2351fs)	TRIO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253086	NM_007118.4(TRIO):c.3239A>T (p.Asn1080Ile)	TRIO	Pathogenic	criteria provided, single submitter
449111	NM_007118.4(TRIO):c.3232C>T (p.Arg1078Trp)	TRIO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
830226	NM_007118.4(TRIO):c.3232C>G (p.Arg1078Gly)	TRIO	Pathogenic	criteria provided, single submitter
830227	NM_007118.4(TRIO):c.3233G>A (p.Arg1078Gln)	TRIO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
976785	NM_007118.4(TRIO):c.4394A>G (p.Asn1465Ser)	TRIO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
978213	NM_007118.4(TRIO):c.4382C>T (p.Pro1461Leu)	TRIO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
981478	NM_007118.4(TRIO):c.4387C>T (p.Arg1463Ter)	TRIO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679335	NM_007118.4(TRIO):c.704del (p.Glu235fs)	TRIO	Likely pathogenic	criteria provided, single submitter
1679364	NM_007118.4(TRIO):c.1665_1666delinsTT (p.Trp555_Gln556delinsCysTer)	TRIO	Likely pathogenic	criteria provided, single submitter
2584353	NM_007118.4(TRIO):c.5619G>A (p.Met1873Ile)	TRIO	Likely pathogenic	criteria provided, single submitter
3238822	NM_007118.4(TRIO):c.5345_5355dup (p.Ser1786fs)	TRIO	Likely pathogenic	criteria provided, single submitter
3366966	NM_007118.4(TRIO):c.5482G>T (p.Glu1828Ter)	TRIO	Likely pathogenic	criteria provided, single submitter
3376172	NM_007118.4(TRIO):c.5822_5823insAG (p.Phe1942fs)	TRIO	Likely pathogenic	criteria provided, single submitter
3382329	NM_007118.4(TRIO):c.1993C>T (p.Gln665Ter)	TRIO	Likely pathogenic	criteria provided, single submitter
3382398	NM_007118.4(TRIO):c.7566_7573dup (p.Arg2525fs)	TRIO	Likely pathogenic	criteria provided, single submitter
3382523	NM_007118.4(TRIO):c.3766-2A>C	TRIO	Likely pathogenic	criteria provided, single submitter
3591863	NM_007118.4(TRIO):c.5497-1G>C	TRIO	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775856	NM_007118.4(TRIO):c.6893_6968del (p.Gly2298fs)	TRIO	Likely pathogenic	criteria provided, single submitter
4294516	NM_007118.4(TRIO):c.1147C>T (p.Gln383Ter)	TRIO	Likely pathogenic	criteria provided, single submitter
978212	NM_007118.4(TRIO):c.3224C>T (p.Thr1075Ile)	TRIO	Likely pathogenic	criteria provided, single submitter
516767	NM_007118.4(TRIO):c.8027A>G (p.Asn2676Ser)	LOC126807323	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
996972	NM_007118.4(TRIO):c.8120G>A (p.Arg2707Gln)	LOC126807323	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1098678	NM_007118.4(TRIO):c.9277C>T (p.Leu3093Phe)	TRIO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1185726	NM_007118.4(TRIO):c.5989G>A (p.Ala1997Thr)	TRIO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805205	NM_007118.4(TRIO):c.6913G>A (p.Gly2305Ser)	TRIO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2504090	NM_007118.4(TRIO):c.4085A>G (p.Tyr1362Cys)	TRIO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
501649	NM_007118.4(TRIO):c.41C>T (p.Ser14Phe)	TRIO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
788726	NM_007118.4(TRIO):c.6877GGC[7] (p.Gly2298dup)	TRIO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
TRIO	Definitive	Autosomal dominant	syndromic intellectual disability	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRIO	Orphanet:476126	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome
ANKH	Orphanet:1416	Familial calcium pyrophosphate deposition
ANKH	Orphanet:1522	Craniometaphyseal dysplasia

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
TRIO	HGNC:12303	ENSG00000038382	O75962	Triple functional domain protein	gencc,clinvar
ANKH	HGNC:15492	ENSG00000154122	Q9HCJ1	Mineralization regulator ANKH	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRIO	Triple functional domain protein	Guanine nucleotide exchange factor (GEF) for RHOA and RAC1 GTPases.
ANKH	Mineralization regulator ANKH	Transports adenosine triphosphate (ATP) and possibly other nucleoside triphosphates (NTPs) from cytosol to the extracellular space.

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRIO	Kinase	yes		DH_dom, Prot_kinase_dom, CRAL-TRIO_dom
ANKH	Other/Unknown	no		ANKH

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
cortical plate	1
stromal cell of endometrium	1
sural nerve	1
inferior vagus X ganglion	1
parotid gland	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRIO	279	ubiquitous	marker	sural nerve, cortical plate, stromal cell of endometrium
ANKH	273	ubiquitous	marker	tibia, parotid gland, inferior vagus X ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRIO	2,892
ANKH	850

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRIO	O75962	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKH	Q9HCJ1	84.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
DCC mediated attractive signaling	1	356.9×	0.027	TRIO
Miscellaneous transport and binding events	1	219.6×	0.027	ANKH
RHOJ GTPase cycle	1	100.2×	0.027	TRIO
NRAGE signals death through JNK	1	92.1×	0.027	TRIO
RHOG GTPase cycle	1	74.2×	0.027	TRIO
G alpha (12/13) signalling events	1	68.8×	0.027	TRIO
RAC2 GTPase cycle	1	63.4×	0.027	TRIO
RAC3 GTPase cycle	1	59.5×	0.027	TRIO
RHOA GTPase cycle	1	37.3×	0.036	TRIO
CDC42 GTPase cycle	1	36.1×	0.036	TRIO
RAC1 GTPase cycle	1	30.5×	0.037	TRIO
G alpha (q) signalling events	1	28.7×	0.037	TRIO
Transport of small molecules	1	12.6×	0.078	ANKH

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
inhibition of non-skeletal tissue mineralization	1	2106.5×	0.004	ANKH
diphosphate metabolic process	1	1685.2×	0.004	ANKH
cementum mineralization	1	1203.7×	0.004	ANKH
cell surface receptor protein tyrosine phosphatase signaling pathway	1	1053.2×	0.004	TRIO
response to sodium phosphate	1	842.6×	0.004	ANKH
ATP export	1	842.6×	0.004	ANKH
phosphate ion transmembrane transport	1	601.9×	0.005	ANKH
phosphate ion homeostasis	1	526.6×	0.005	ANKH
regulation of bone mineralization	1	366.4×	0.006	ANKH
postsynaptic modulation of chemical synaptic transmission	1	337.0×	0.006	TRIO
muscle cell cellular homeostasis	1	324.1×	0.006	ANKH
calcium ion homeostasis	1	221.7×	0.008	ANKH
negative regulation of fat cell differentiation	1	156.0×	0.010	TRIO
neuron projection morphogenesis	1	138.1×	0.010	TRIO
bone mineralization	1	135.9×	0.010	ANKH
locomotory behavior	1	89.6×	0.015	ANKH
transmembrane transport	1	84.3×	0.015	ANKH
regulation of small GTPase mediated signal transduction	1	72.0×	0.016	TRIO
skeletal system development	1	62.9×	0.018	ANKH
axon guidance	1	45.3×	0.023	TRIO
gene expression	1	39.9×	0.025	ANKH

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
TRIO	0	0
ANKH	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
TRIO	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	1	TRIO
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ANKH

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)
TRIO	2	—
ANKH	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.