Intellectual disability, autosomal dominant 55, with seizures

Summary

Intellectual disability, autosomal dominant 55, with seizures (MONDO:0030921) is a disease caused by NUS1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: NUS1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 44

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 55, with seizures
Mondo ID	MONDO:0030921
OMIM	617831
DOID	DOID:0080227
UMLS	C4693371
MedGen	1635938
GARD	0016260
Is cancer (heuristic)	no

Also known as: autosomal dominant mental retardation 55 · intellectual disability, autosomal dominant 55, with seizures · mental retardation, autosomal dominant 55, with seizures · MRD55

Data availability: 44 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 55, with seizures

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 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

44 retrieved; paginated sample, class counts are floors:

16 pathogenic, 13 likely pathogenic, 8 uncertain significance, 3 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2579265	GRCh38/hg38 6q21-23.1(chr6:113857248-130442177)x1	ARHGAP18	Pathogenic	criteria provided, single submitter
487688	NC_000006.12:g.(117676084_117693041)_(117693166_117694030)del	LOC129389624	Pathogenic	no assertion criteria provided
1357547	NM_138459.5(NUS1):c.719T>G (p.Leu240Ter)	NUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699400	NM_138459.5(NUS1):c.99G>A (p.Trp33Ter)	NUS1	Pathogenic	criteria provided, single submitter
1878519	NM_138459.5(NUS1):c.405C>G (p.Tyr135Ter)	NUS1	Pathogenic	criteria provided, single submitter
2430036	NM_138459.5(NUS1):c.328C>T (p.Gln110Ter)	NUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2505167	NM_138459.5(NUS1):c.791+6T>G	NUS1	Pathogenic	no assertion criteria provided
2506517	NM_138459.5(NUS1):c.48_49del (p.Cys17fs)	NUS1	Pathogenic	criteria provided, single submitter
2577019	NM_138459.5(NUS1):c.128_141del (p.Ala43fs)	NUS1	Pathogenic	criteria provided, single submitter
2583160	NM_138459.5(NUS1):c.472G>T (p.Glu158Ter)	NUS1	Pathogenic	criteria provided, single submitter
3254587	NM_138459.5(NUS1):c.647dup (p.Arg217fs)	NUS1	Pathogenic	criteria provided, single submitter
3770205	NM_138459.5(NUS1):c.279del (p.Leu94fs)	NUS1	Pathogenic	criteria provided, single submitter
4685557	NM_138459.5(NUS1):c.646_647del (p.Lys216fs)	NUS1	Pathogenic	criteria provided, single submitter
487686	NM_138459.5(NUS1):c.743del (p.Asp248fs)	NUS1	Pathogenic	no assertion criteria provided
487687	NM_138459.5(NUS1):c.128_141dup (p.Val48fs)	NUS1	Pathogenic	criteria provided, multiple submitters, no conflicts
807644	NM_138459.5(NUS1):c.238_263del (p.Ala80fs)	NUS1	Pathogenic	criteria provided, single submitter
981034	NM_138459.5(NUS1):c.734G>T (p.Gly245Val)	NUS1	Pathogenic	criteria provided, single submitter
981035	NM_138459.5(NUS1):c.752T>G (p.Leu251Ter)	NUS1	Pathogenic	criteria provided, single submitter
981036	NM_138459.5(NUS1):c.415+1G>A	NUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329959	NM_138459.5(NUS1):c.26G>A (p.Trp9Ter)	NUS1	Likely pathogenic	criteria provided, single submitter
1334062	NM_138459.5(NUS1):c.692-2A>G	NUS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1709668	NM_138459.5(NUS1):c.220_244del (p.Gly74fs)	NUS1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2576546	NM_138459.5(NUS1):c.677dup (p.Leu226fs)	NUS1	Likely pathogenic	criteria provided, single submitter
3024536	NM_138459.5(NUS1):c.439A>T (p.Arg147Ter)	NUS1	Likely pathogenic	criteria provided, single submitter
3236086	NM_138459.5(NUS1):c.415+2_415+3insCGTAGGT	NUS1	Likely pathogenic	criteria provided, single submitter
3236093	NM_138459.5(NUS1):c.792-2A>G	NUS1	Likely pathogenic	criteria provided, single submitter
3359086	NM_138459.5(NUS1):c.791+4A>C	NUS1	Likely pathogenic	criteria provided, single submitter
3382529	NM_138459.5(NUS1):c.861T>A (p.Cys287Ter)	NUS1	Likely pathogenic	criteria provided, single submitter
3770204	NM_138459.5(NUS1):c.640A>T (p.Lys214Ter)	NUS1	Likely pathogenic	criteria provided, single submitter
3776132	NM_138459.5(NUS1):c.314dup (p.Thr106fs)	NUS1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
NUS1	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 55, with seizures	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NUS1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

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
NUS1	HGNC:21042	ENSG00000153989	Q96E22	Dehydrodolichyl diphosphate synthase complex subunit NUS1	gencc,clinvar
ARHGAP18	HGNC:21035	ENSG00000146376	Q8N392	Rho GTPase-activating protein 18	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NUS1	Dehydrodolichyl diphosphate synthase complex subunit NUS1	With DHDDS, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery.
ARHGAP18	Rho GTPase-activating protein 18	Rho GTPase activating protein that suppresses F-actin polymerization by inhibiting Rho.

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NUS1	Enzyme (other)	yes	2.5.1.87	UPP_synth-like, UPP_synth-like_sf, Nus1/NgBR
ARHGAP18	Other/Unknown	no		RhoGAP_dom, Rho_GTPase_activation_prot, RHG40/28/18_ubiquitin

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
endometrium	1
islet of Langerhans	1
tibia	1
bronchial epithelial cell	1
germinal epithelium of ovary	1
oviduct epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NUS1	255	broad	marker	endometrium, tibia, islet of Langerhans
ARHGAP18	254	ubiquitous	marker	germinal epithelium of ovary, oviduct epithelium, bronchial epithelial cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NUS1	2,058
ARHGAP18	1,113

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NUS1	Q96E22	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARHGAP18	Q8N392	75.05

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
Defective DHDDS causes RP59	1	2855.0×	0.001	NUS1
Synthesis of dolichyl-phosphate	1	815.7×	0.002	NUS1
RHOC GTPase cycle	1	73.2×	0.018	ARHGAP18
RHOA GTPase cycle	1	37.3×	0.027	ARHGAP18

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
dolichyl diphosphate biosynthetic process	1	4213.0×	0.004	NUS1
regulation of intracellular cholesterol transport	1	2106.5×	0.004	NUS1
dolichyl monophosphate biosynthetic process	1	936.2×	0.004	NUS1
positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	842.6×	0.004	NUS1
vascular endothelial growth factor signaling pathway	1	526.6×	0.005	NUS1
regulation of cell motility	1	495.6×	0.005	ARHGAP18
positive regulation of cell migration involved in sprouting angiogenesis	1	366.4×	0.006	NUS1
regulation of actin filament polymerization	1	290.6×	0.006	ARHGAP18
small GTPase-mediated signal transduction	1	91.6×	0.017	ARHGAP18
regulation of actin cytoskeleton organization	1	78.8×	0.017	ARHGAP18
cholesterol homeostasis	1	78.0×	0.017	NUS1
regulation of small GTPase mediated signal transduction	1	72.0×	0.017	ARHGAP18
regulation of cell shape	1	61.5×	0.019	ARHGAP18
angiogenesis	1	31.2×	0.034	NUS1
cell differentiation	1	14.6×	0.068	NUS1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NUS1	0	0
ARHGAP18	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NUS1	2.5.1.87	ditrans,polycis-polyprenyl diphosphate synthase [(2E,6E)-farnesyl diphosphate specific]

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	NUS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ARHGAP18

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)
NUS1	0	—
ARHGAP18	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.