Intellectual disability, autosomal dominant 43

Summary

Intellectual disability, autosomal dominant 43 (MONDO:0014858) is a disease caused by HIVEP2 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Causal gene: HIVEP2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 174
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 43
Mondo ID	MONDO:0014858
OMIM	616977
DOID	DOID:0070073
SNOMED CT	765434008
UMLS	C4707429
MedGen	1640004
GARD	0013179
Is cancer (heuristic)	no

Also known as: autosomal dominant intellectual disability 43 · autosomal dominant intellectual disability-43 · autosomal dominant non-syndromic intellectual disability caused by mutation in HIVEP2 · HIVEP2 autosomal dominant non-syndromic intellectual disability · HIVEP2-related intellectual disability · intellectual disability, autosomal dominant 43 · intellectual disability, autosomal dominant type 43 · mental retardation, autosomal dominant 43 · mental retardation, autosomal dominant type 43 · MRD43

Data availability: 174 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 43

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 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

174 retrieved; paginated sample, class counts are floors:

94 uncertain significance, 27 pathogenic, 21 conflicting classifications of pathogenicity, 14 likely pathogenic, 8 likely benign, 6 benign/likely benign, 2 benign, 1 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1184547	NM_006734.4(HIVEP2):c.2853_2854del (p.Glu953fs)	HIVEP2	Pathogenic	no assertion criteria provided
1298289	NM_006734.4(HIVEP2):c.5890G>T (p.Gly1964Ter)	HIVEP2	Pathogenic	criteria provided, single submitter
1685875	NM_006734.4(HIVEP2):c.5791dup (p.Thr1931fs)	HIVEP2	Pathogenic	criteria provided, single submitter
1700005	NM_006734.4(HIVEP2):c.5856dup (p.Val1953fs)	HIVEP2	Pathogenic	criteria provided, single submitter
224791	NM_006734.4(HIVEP2):c.2827C>T (p.Arg943Ter)	HIVEP2	Pathogenic	criteria provided, multiple submitters, no conflicts
224792	NM_006734.4(HIVEP2):c.2905C>T (p.Gln969Ter)	HIVEP2	Pathogenic	criteria provided, single submitter
224793	NM_006734.4(HIVEP2):c.6475G>T (p.Gly2159Ter)	HIVEP2	Pathogenic	no assertion criteria provided
224794	NM_006734.4(HIVEP2):c.2857G>T (p.Glu953Ter)	HIVEP2	Pathogenic	criteria provided, single submitter
224795	NM_006734.4(HIVEP2):c.5614dup (p.Glu1872fs)	HIVEP2	Pathogenic	criteria provided, single submitter
224798	NM_006734.4(HIVEP2):c.1189G>T (p.Asp397Tyr)	HIVEP2	Pathogenic	criteria provided, single submitter
236210	NM_006734.4(HIVEP2):c.5737del (p.Asp1913fs)	HIVEP2	Pathogenic	no assertion criteria provided
236212	NM_006734.4(HIVEP2):c.3556C>T (p.Gln1186Ter)	HIVEP2	Pathogenic	no assertion criteria provided
2626990	NM_006734.4(HIVEP2):c.868G>T (p.Glu290Ter)	HIVEP2	Pathogenic	criteria provided, single submitter
3024316	NM_006734.4(HIVEP2):c.5653A>T (p.Lys1885Ter)	HIVEP2	Pathogenic	criteria provided, single submitter
3062061	NM_006734.4(HIVEP2):c.5764del (p.Asp1922fs)	HIVEP2	Pathogenic	criteria provided, single submitter
3236242	NM_006734.4(HIVEP2):c.3412C>T (p.Gln1138Ter)	HIVEP2	Pathogenic	criteria provided, multiple submitters, no conflicts
3382760	NM_006734.4(HIVEP2):c.5994C>G (p.Tyr1998Ter)	HIVEP2	Pathogenic	criteria provided, single submitter
422837	NM_006734.4(HIVEP2):c.5900del (p.Ser1967fs)	HIVEP2	Pathogenic	criteria provided, single submitter
4532015	NM_006734.4(HIVEP2):c.5176C>T (p.Gln1726Ter)	HIVEP2	Pathogenic	criteria provided, single submitter
4820213	NM_006734.4(HIVEP2):c.5762_5763del (p.Asp1920_Phe1921insTer)	HIVEP2	Pathogenic	criteria provided, single submitter
520986	NM_006734.4(HIVEP2):c.6964C>T (p.Gln2322Ter)	HIVEP2	Pathogenic	criteria provided, single submitter
523775	NM_006734.4(HIVEP2):c.5935C>T (p.Arg1979Ter)	HIVEP2	Pathogenic	criteria provided, multiple submitters, no conflicts
620051	NM_006734.4(HIVEP2):c.3461_3492dup (p.Glu1165fs)	HIVEP2	Pathogenic	criteria provided, single submitter
620226	NM_006734.4(HIVEP2):c.6667C>T (p.Arg2223Ter)	HIVEP2	Pathogenic	criteria provided, multiple submitters, no conflicts
620259	NM_006734.4(HIVEP2):c.3742C>T (p.Gln1248Ter)	HIVEP2	Pathogenic	criteria provided, single submitter
984807	NM_006734.4(HIVEP2):c.5686C>T (p.Gln1896Ter)	HIVEP2	Pathogenic	no assertion criteria provided
4819224	Single allele	LOC129997343	Pathogenic	criteria provided, single submitter
127118	NM_005051.3(QARS1):c.1543C>T (p.Arg515Trp)	QARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1992350	NM_006734.4(HIVEP2):c.2367del (p.Gly791fs)	HIVEP2	Likely pathogenic	criteria provided, single submitter
2499583	NM_006734.4(HIVEP2):c.117del (p.Phe39fs)	HIVEP2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
HIVEP2	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 43	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HIVEP2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
HYDIN	Orphanet:244	Primary ciliary dyskinesia
QARS1	Orphanet:404437	Diffuse cerebral and cerebellar atrophy-intractable seizures-progressive microcephaly syndrome
QARS1	Orphanet:423306	Microcephaly-short stature-intellectual disability-facial dysmorphism syndrome

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
HIVEP2	HGNC:4921	ENSG00000010818	P31629	Transcription factor HIVEP2	gencc,clinvar
HYDIN	HGNC:19368	ENSG00000157423	Q4G0P3	Hydrocephalus-inducing protein homolog	clinvar
QARS1	HGNC:9751	ENSG00000172053	P47897	Glutamine–tRNA ligase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HIVEP2	Transcription factor HIVEP2	This protein specifically binds to the DNA sequence 5’-GGGACTTTCC-3’ which is found in the enhancer elements of numerous viral promoters such as those of SV40, CMV, or HIV1.
HYDIN	Hydrocephalus-inducing protein homolog	Required for ciliary motility.
QARS1	Glutamine–tRNA ligase	Glutamine–tRNA ligase.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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
Antibody/Immunoglobulin	1	9.7×	0.298
Enzyme (other)	1	4.0×	0.321
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HIVEP2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf,
HYDIN	Antibody/Immunoglobulin	yes		Ig-like_fold, P-loop_NTPase, Hydin-like
QARS1	Enzyme (other)	yes	6.1.1.18	Glu/Gln-tRNA-synth, aa-tRNA-synth_I_CS, Gln-tRNA-synth

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
lateral nuclear group of thalamus	1
tendon of biceps brachii	1
vena cava	1
corpus callosum	1
male germ line stem cell (sensu Vertebrata) in testis	1
right uterine tube	1
mammalian vulva	1
primordial germ cell in gonad	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HIVEP2	296	ubiquitous	marker	tendon of biceps brachii, vena cava, lateral nuclear group of thalamus
HYDIN	136	broad	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, corpus callosum
QARS1	299	ubiquitous	marker	mammalian vulva, upper arm skin, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
QARS1	4,405
HIVEP2	1,489
HYDIN	1,412

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
QARS1	P47897	4
HYDIN	Q4G0P3	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HIVEP2	P31629	36.43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Mitochondrial tRNA aminoacylation	1	519.1×	0.012	QARS1
Cytosolic tRNA aminoacylation	1	439.2×	0.012	QARS1
tRNA Aminoacylation	1	285.5×	0.012	QARS1
Selenoamino acid metabolism	1	196.9×	0.012	QARS1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.012	QARS1
MITF-M-regulated melanocyte development	1	114.2×	0.016	QARS1
Metabolism of amino acids and derivatives	1	67.6×	0.022	QARS1
Translation	1	62.1×	0.022	QARS1
Developmental Biology	1	14.5×	0.085	QARS1
Metabolism of proteins	1	12.4×	0.086	QARS1
Metabolism	1	11.6×	0.086	QARS1

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
glutaminyl-tRNA aminoacylation	1	2808.7×	0.003	QARS1
trachea development	1	1872.4×	0.003	HYDIN
axonemal central apparatus assembly	1	936.2×	0.005	HYDIN
negative regulation of stress-activated MAPK cascade	1	561.7×	0.005	QARS1
epithelial cell development	1	510.7×	0.005	HYDIN
tRNA aminoacylation for protein translation	1	280.9×	0.007	QARS1
ventricular system development	1	280.9×	0.007	HYDIN
negative regulation of apoptotic signaling pathway	1	187.2×	0.009	QARS1
cilium movement	1	130.6×	0.011	HYDIN
brain development	1	26.5×	0.044	QARS1
actin cytoskeleton organization	1	26.4×	0.044	HYDIN
negative regulation of DNA-templated transcription	1	10.5×	0.100	QARS1
regulation of transcription by RNA polymerase II	1	3.9×	0.236	HIVEP2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HIVEP2	0	0
HYDIN	0	0
QARS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
QARS1	6	Binding:6
HIVEP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
QARS1	6.1.1.18	glutamine-tRNA ligase

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	2	HYDIN, QARS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HIVEP2

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)
HIVEP2	1	—
HYDIN	0	—
QARS1	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01238250	Not specified	RECRUITING	Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight