Intellectual developmental disorder, autosomal recessive 68

Summary

Intellectual developmental disorder, autosomal recessive 68 (MONDO:0032665) is a disease caused by TRMT1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: TRMT1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 32

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder, autosomal recessive 68
Mondo ID	MONDO:0032665
OMIM	618302
DOID	DOID:0081229
UMLS	C4749033
MedGen	1648490
GARD	0025718
Is cancer (heuristic)	no

Also known as: MRT68

Data availability: 32 ClinVar variants · 5 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 developmental disorder, autosomal recessive 68

Related subtypes (67): intellectual disability, autosomal recessive 1, intellectual disability, autosomal recessive 2, 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 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

32 retrieved; paginated sample, class counts are floors:

11 likely pathogenic, 10 uncertain significance, 8 pathogenic, 2 conflicting classifications of pathogenicity, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1708177	NM_001136035.4(TRMT1):c.458del (p.Gly153fs)	TRMT1	Pathogenic	no assertion criteria provided
3024215	NM_001136035.4(TRMT1):c.1630C>T (p.Arg544Ter)	TRMT1	Pathogenic	criteria provided, single submitter
3063891	NM_001136035.4(TRMT1):c.1639G>T (p.Gly547Ter)	TRMT1	Pathogenic	criteria provided, single submitter
3339129	NM_001136035.4(TRMT1):c.713del (p.Pro238fs)	TRMT1	Pathogenic	criteria provided, single submitter
617602	NM_001136035.4(TRMT1):c.657_688del (p.Gln219fs)	TRMT1	Pathogenic	criteria provided, multiple submitters, no conflicts
617603	NM_001136035.4(TRMT1):c.1506+1G>T	TRMT1	Pathogenic	no assertion criteria provided
617604	NM_001136035.4(TRMT1):c.1332_1333del (p.Tyr445fs)	TRMT1	Pathogenic	criteria provided, multiple submitters, no conflicts
982958	NM_001136035.4(TRMT1):c.312del (p.Lys105fs)	TRMT1	Pathogenic	criteria provided, single submitter
3765818	NM_001136035.4(TRMT1):c.1584-834_1584-2del	LOC130063689	Likely pathogenic	criteria provided, single submitter
1164054	NM_001136035.4(TRMT1):c.232C>T (p.Gln78Ter)	TRMT1	Likely pathogenic	no assertion criteria provided
1328940	NM_001136035.4(TRMT1):c.311-1G>A	TRMT1	Likely pathogenic	no assertion criteria provided
1339204	NM_001136035.4(TRMT1):c.1487G>A (p.Trp496Ter)	TRMT1	Likely pathogenic	criteria provided, single submitter
191099	NM_001136035.4(TRMT1):c.967C>T (p.Arg323Cys)	TRMT1	Likely pathogenic	criteria provided, single submitter
2429090	NM_001136035.4(TRMT1):c.35del (p.Phe12fs)	TRMT1	Likely pathogenic	criteria provided, single submitter
2502435	NM_001136035.4(TRMT1):c.24_33del (p.Leu10fs)	TRMT1	Likely pathogenic	criteria provided, single submitter
2582353	NM_001136035.4(TRMT1):c.1161_1162del (p.Cys387fs)	TRMT1	Likely pathogenic	criteria provided, single submitter
444449	NM_001136035.4(TRMT1):c.389_390del (p.Lys130fs)	TRMT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4795242	NM_001136035.4(TRMT1):c.1435_1436del (p.Ser479fs)	TRMT1	Likely pathogenic	criteria provided, single submitter
997949	NM_001136035.4(TRMT1):c.1534C>T (p.Arg512Ter)	TRMT1	Likely pathogenic	criteria provided, single submitter
1695573	NM_001136035.4(TRMT1):c.310+5G>C	TRMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3573517	NM_001136035.4(TRMT1):c.1581del (p.Arg528fs)	TRMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029137	NM_001136035.4(TRMT1):c.1019+9G>C	TRMT1	Uncertain significance	criteria provided, single submitter
1029138	NM_001136035.4(TRMT1):c.1078G>A (p.Gly360Ser)	TRMT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029139	NM_001136035.4(TRMT1):c.1833G>A (p.Glu611=)	TRMT1	Uncertain significance	criteria provided, single submitter
1029140	NM_001136035.4(TRMT1):c.583C>T (p.Arg195Trp)	TRMT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029141	NM_001136035.4(TRMT1):c.814A>G (p.Thr272Ala)	TRMT1	Uncertain significance	criteria provided, single submitter
1325620	NM_001136035.4(TRMT1):c.21G>A (p.Trp7Ter)	TRMT1	Uncertain significance	criteria provided, single submitter
1706460	NM_001136035.4(TRMT1):c.1834-7C>T	TRMT1	Uncertain significance	criteria provided, single submitter
2277768	NM_001136035.4(TRMT1):c.1202_1204dup (p.Pro401_Ile402insThr)	TRMT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2374198	NM_001136035.4(TRMT1):c.1054G>A (p.Gly352Arg)	TRMT1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
TRMT1	Definitive	Autosomal recessive	intellectual developmental disorder, autosomal recessive 68	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRMT1	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TRMT1	HGNC:25980	ENSG00000104907	Q9NXH9	tRNA (guanine(26)-N(2))-dimethyltransferase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRMT1	tRNA (guanine(26)-N(2))-dimethyltransferase	Dimethylates a single guanine residue at position 26 of most nuclear- and mitochondrial-encoded tRNAs using S-adenosyl-L-methionine as donor of the methyl groups. tRNA guanine(26)-dimethylation is required for redox homeostasis and ensure…

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRMT1	Transcription factor	no		Znf_CCCH, Trm1, SAM-dependent_MTases_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
left ovary	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRMT1	230	ubiquitous	marker	lower esophagus mucosa, granulocyte, left ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRMT1	1,890

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRMT1	Q9NXH9	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
tRNA modification in the nucleus and cytosol	1	292.8×	0.003	TRMT1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tRNA N2-guanine methylation	1	8426.0×	2e-04	TRMT1
tRNA modification	1	601.9×	0.002	TRMT1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRMT1	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
TRMT1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TRMT1

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)
TRMT1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.