Intellectual disability, autosomal recessive 2

Summary

Intellectual disability, autosomal recessive 2 (MONDO:0011828) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal recessive 2
Mondo ID	MONDO:0011828
MeSH	C564404
OMIM	607417
DOID	DOID:0081178
UMLS	C1843942
MedGen	334541
GARD	0022538
Is cancer (heuristic)	no

Also known as: autosomal recessive non-syndromic intellectual disability caused by mutation in CRBN · CRBN autosomal recessive non-syndromic intellectual disability · intellectual disability, autosomal recessive 2 · intellectual disability, autosomal recessive type 2 · mental retardation, autosomal recessive 2 · mental retardation, autosomal recessive 2A · mental retardation, autosomal recessive type 2 · MRT2

Data availability: 14 ClinVar variants · 2 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 recessive non-syndromic intellectual disability › intellectual disability, autosomal recessive 2

Related subtypes (67): intellectual disability, autosomal recessive 1, intellectual disability, autosomal recessive 3, intellectual disability, autosomal recessive 12, intellectual disability, autosomal recessive 5, intellectual disability, autosomal recessive 6, intellectual disability, autosomal recessive 7, intellectual disability, autosomal recessive 9, intellectual disability, autosomal recessive 10, intellectual disability, autosomal recessive 11, intellectual disability, autosomal recessive 4, intellectual disability, autosomal recessive 13, intellectual disability, autosomal recessive 14, Rafiq syndrome, intellectual disability, autosomal recessive 16, intellectual disability, autosomal recessive 18, intellectual disability, autosomal recessive 31, intellectual disability, autosomal recessive 29, intellectual disability, autosomal recessive 27, intellectual disability, autosomal recessive 33, intellectual disability, autosomal recessive 30, intellectual disability, autosomal recessive 19, intellectual disability, autosomal recessive 23, intellectual disability, autosomal recessive 24, intellectual disability, autosomal recessive 25, intellectual disability, autosomal recessive 28, intellectual disability, autosomal recessive 34, intellectual disability, autosomal recessive 42, intellectual disability, autosomal recessive 43, intellectual disability, autosomal recessive 44, intellectual disability, autosomal recessive 45, intellectual disability, autosomal recessive 46, intellectual disability, autosomal recessive 47, Al-Raqad syndrome, intellectual disability, autosomal recessive 50, intellectual disability, autosomal recessive 51, intellectual disability, autosomal recessive 52, intellectual disability, autosomal recessive 54, intellectual disability, autosomal recessive 56, intellectual developmental disorder, autosomal recessive 74, intellectual disability, autosomal recessive 57, intellectual disability, autosomal recessive 58, intellectual disability, autosomal recessive 59, pontocerebellar hypoplasia type 1, intellectual disability, autosomal recessive 64, intellectual disability, autosomal recessive 65, intellectual developmental disorder, autosomal recessive 73, intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly, intellectual disability, autosomal recessive 61, intellectual developmental disorder, autosomal recessive 76, intellectual developmental disorder, autosomal recessive 77, intellectual disability, autosomal recessive 66, intellectual developmental disorder, autosomal recessive 67, intellectual developmental disorder, autosomal recessive 68, intellectual developmental disorder, autosomal recessive 69, intellectual developmental disorder, autosomal recessive 70, intellectual developmental disorder, autosomal recessive 71, intellectual developmental disorder, autosomal recessive 72, glycosylphosphatidylinositol biosynthesis defect 16, intellectual disability, autosomal recessive 60, intellectual disability, autosomal recessive 63, adenosine kinase deficiency, intellectual developmental disorder, autosomal recessive 78, intellectual developmental disorder, autosomal recessive 79, intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly, intellectual developmental disorder, autosomal recessive 81, intellectual developmental disorder, autosomal recessive 82, intellectual developmental disorder, autosomal recessive 83

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

14 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 pathogenic, 3 benign, 2 conflicting classifications of pathogenicity, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1032731	NM_016302.4(CRBN):c.433C>T (p.Arg145Ter)	CRBN	Pathogenic	criteria provided, multiple submitters, no conflicts
1321315	NM_016302.4(CRBN):c.129dup (p.Pro44fs)	CRBN	Pathogenic	no assertion criteria provided
984705	NM_016302.4(CRBN):c.835+1G>A	CRBN	Pathogenic	criteria provided, single submitter
816985	NM_016302.4(CRBN):c.641C>G (p.Ser214Ter)	CRBN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
209144	NM_016302.4(CRBN):c.1171T>C (p.Cys391Arg)	TRNT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1821	NM_016302.4(CRBN):c.1255C>T (p.Arg419Ter)	CRBN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
758080	NM_016302.4(CRBN):c.724C>T (p.Arg242Cys)	CRBN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028016	NM_016302.4(CRBN):c.40A>T (p.Met14Leu)	CRBN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1032730	NM_016302.4(CRBN):c.29C>G (p.Ala10Gly)	CRBN	Uncertain significance	criteria provided, single submitter
2441986	NM_016302.4(CRBN):c.94G>A (p.Glu32Lys)	CRBN	Uncertain significance	criteria provided, multiple submitters, no conflicts
3362774	NM_016302.4(CRBN):c.1034C>T (p.Pro345Leu)	CRBN	Uncertain significance	criteria provided, single submitter
1255409	NM_016302.4(CRBN):c.750+32A>G	CRBN	Benign	criteria provided, multiple submitters, no conflicts
128855	NM_016302.4(CRBN):c.175-9T>C	CRBN	Benign	criteria provided, multiple submitters, no conflicts
128857	NM_016302.4(CRBN):c.735T>C (p.Tyr245=)	CRBN	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
CRBN	Supportive	Autosomal recessive	autosomal recessive non-syndromic intellectual disability	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CRBN	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
TRNT1	Orphanet:369861	Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay 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
CRBN	HGNC:30185	ENSG00000113851	Q96SW2	Protein cereblon	gencc,clinvar
TRNT1	HGNC:17341	ENSG00000072756	Q96Q11	CCA tRNA nucleotidyltransferase 1, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRBN	Protein cereblon	Substrate recognition component of a DCX (DDB1-CUL4-X-box) E3 protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as MEIS2, ILF2 or GLUL.
TRNT1	CCA tRNA nucleotidyltransferase 1, mitochondrial	Nucleotidyltransferase that catalyzes the addition and repair of the essential 3’-terminal CCA sequence in tRNAs, which is necessary for the attachment of amino acids to the 3’ terminus of tRNA molecules, using CTP and ATP as substrates. t…

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)
CRBN	Other/Unknown	no		Lon_prtase_N, Yippee/Mis18/Cereblon, PUA-like_sf
TRNT1	Enzyme (other)	yes	2.7.7.72	PolA_pol_head_dom, PolyA_RNA-bd, NT_sf

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
Brodmann (1909) area 23	1
calcaneal tendon	1
skin of hip	1
endothelial cell	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRBN	288	ubiquitous	marker	calcaneal tendon, Brodmann (1909) area 23, skin of hip
TRNT1	254	ubiquitous	marker	endothelial cell, secondary oocyte, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRNT1	2,982
CRBN	2,201

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CRBN	Q96SW2	90
TRNT1	Q96Q11	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
tRNA processing in the mitochondrion	1	1142.0×	0.003	TRNT1
tRNA processing in the nucleus	1	98.5×	0.015	TRNT1
Potential therapeutics for SARS	1	57.1×	0.017	CRBN

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
tRNA 3’-terminal CCA addition	1	8426.0×	8e-04	TRNT1
tRNA surveillance	1	8426.0×	8e-04	TRNT1
negative regulation of monoatomic ion transmembrane transport	1	2808.7×	0.002	CRBN
mitochondrial tRNA 3’-end processing	1	2106.5×	0.002	TRNT1
tRNA 3’-end processing	1	1685.2×	0.002	TRNT1
locomotory exploration behavior	1	495.6×	0.004	CRBN
rescue of stalled cytosolic ribosome	1	240.7×	0.007	TRNT1
negative regulation of protein-containing complex assembly	1	227.7×	0.007	CRBN
limb development	1	205.5×	0.007	CRBN
positive regulation of Wnt signaling pathway	1	191.5×	0.007	CRBN
positive regulation of protein-containing complex assembly	1	168.5×	0.007	CRBN
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.041	CRBN
protein ubiquitination	1	20.7×	0.048	CRBN

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CRBN	DASABUVIR

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CRBN	18	4
TRNT1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DASABUVIR	4	CRBN
POMALIDOMIDE	4	CRBN
THALIDOMIDE	4	CRBN
LENALIDOMIDE	4	CRBN
PONATINIB	4	CRBN
ASCIMINIB	4	CRBN
BRIGATINIB	4	CRBN
CRIZOTINIB	4	CRBN
IBERDOMIDE	3	CRBN
URACIL	3	CRBN
VEPDEGESTRANT	3	CRBN
MEZIGDOMIDE	3	CRBN
AVADOMIDE	2	CRBN
E-7820	2	CRBN
INDISULAM	2	CRBN
ADAVOSERTIB	2	CRBN
FORETINIB	2	CRBN
CC-11006	1	CRBN

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CRBN	5,948	Binding:5779, Functional:154, ADMET:15

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TRNT1	2.7.7.72	CCA tRNA nucleotidyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CRBN	5,948

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

18 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)
DASABUVIR	4	CRBN
POMALIDOMIDE	4	CRBN
THALIDOMIDE	4	CRBN
LENALIDOMIDE	4	CRBN
PONATINIB	4	CRBN
ASCIMINIB	4	CRBN
BRIGATINIB	4	CRBN
CRIZOTINIB	4	CRBN
IBERDOMIDE	3	CRBN
URACIL	3	CRBN
VEPDEGESTRANT	3	CRBN
MEZIGDOMIDE	3	CRBN
AVADOMIDE	2	CRBN
E-7820	2	CRBN
INDISULAM	2	CRBN
ADAVOSERTIB	2	CRBN
FORETINIB	2	CRBN
CC-11006	1	CRBN

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CRBN
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TRNT1
D	Druggable family + AlphaFold only, no drug	0
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)
TRNT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.