Intellectual disability, autosomal dominant 41

Summary

Intellectual disability, autosomal dominant 41 (MONDO:0014842) is a disease caused by TBL1XR1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: TBL1XR1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 68

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, autosomal dominant 41
Mondo ID	MONDO:0014842
OMIM	616944
DOID	DOID:0070071
UMLS	C4310784
MedGen	934751
GARD	0025023
Is cancer (heuristic)	no

Also known as: autosomal dominant intellectual disability 41 · autosomal dominant non-syndromic intellectual disability caused by mutation in TBL1XR1 · intellectual disability, autosomal dominant 41 · intellectual disability, autosomal dominant type 41 · mental retardation, autosomal dominant 41 · mental retardation, autosomal dominant type 41 · MRD41 · TBL1XR1 autosomal dominant non-syndromic intellectual disability

Data availability: 68 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 41

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 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, 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

68 retrieved; paginated sample, class counts are floors:

23 likely pathogenic, 20 uncertain significance, 11 pathogenic, 6 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 1 benign, 1 not provided, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
372701	NM_024665.7(TBL1XR1):c.1108G>A (p.Asp370Asn)	LOC126806878	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
666258	NM_024665.7(TBL1XR1):c.1000T>C (p.Cys334Arg)	LOC126806878	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1018524	NM_024665.7(TBL1XR1):c.205-7A>G	TBL1XR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1164048	NM_024665.7(TBL1XR1):c.597_600del (p.Ser199fs)	TBL1XR1	Pathogenic	no assertion criteria provided
1330245	NM_024665.7(TBL1XR1):c.419dup (p.Ile141fs)	TBL1XR1	Pathogenic	criteria provided, single submitter
225872	NM_024665.7(TBL1XR1):c.1189del (p.Ile397fs)	TBL1XR1	Pathogenic	no assertion criteria provided
225873	NM_024665.7(TBL1XR1):c.734A>G (p.Tyr245Cys)	TBL1XR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2443985	NM_024665.7(TBL1XR1):c.697T>A (p.Trp233Arg)	TBL1XR1	Pathogenic	no assertion criteria provided
2581100	NM_024665.7(TBL1XR1):c.420dup (p.Ile141fs)	TBL1XR1	Pathogenic	criteria provided, single submitter
3254814	NM_024665.7(TBL1XR1):c.1331C>T (p.Pro444Leu)	TBL1XR1	Pathogenic	criteria provided, single submitter
4535957	NM_024665.7(TBL1XR1):c.160C>T (p.Gln54Ter)	TBL1XR1	Pathogenic	criteria provided, single submitter
4820315	NM_024665.7(TBL1XR1):c.1372_1387dup (p.Asp463delinsGlyLysTrpPhePheTer)	TBL1XR1	Pathogenic	criteria provided, single submitter
559571	NM_024665.7(TBL1XR1):c.1336T>G (p.Tyr446Asp)	TBL1XR1	Pathogenic	criteria provided, single submitter
807509	NM_024665.7(TBL1XR1):c.799G>T (p.Gly267Cys)	TBL1XR1	Pathogenic	criteria provided, single submitter
981384	NM_024665.7(TBL1XR1):c.1291C>T (p.Arg431Ter)	TBL1XR1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
559628	NM_024665.7(TBL1XR1):c.874dup (p.Ile292fs)	TBL1XR1-AS1	Pathogenic	no assertion criteria provided
1708492	NM_024665.7(TBL1XR1):c.937G>A (p.Asp313Asn)	LOC126806878	Likely pathogenic	criteria provided, single submitter
431083	NM_024665.7(TBL1XR1):c.977G>T (p.Ser326Ile)	LOC126806878	Likely pathogenic	no assertion criteria provided
666259	NM_024665.7(TBL1XR1):c.1043A>G (p.His348Arg)	LOC126806878	Likely pathogenic	criteria provided, multiple submitters, no conflicts
976675	NM_024665.7(TBL1XR1):c.973_975dup (p.Cys325dup)	LOC126806878	Likely pathogenic	criteria provided, single submitter
1184880	NM_024665.7(TBL1XR1):c.1182_1183dup (p.Tyr395fs)	TBL1XR1	Likely pathogenic	criteria provided, single submitter
1188842	NM_024665.7(TBL1XR1):c.1378G>A (p.Gly460Ser)	TBL1XR1	Likely pathogenic	no assertion criteria provided
1228378	NM_024665.7(TBL1XR1):c.1453G>A (p.Gly485Arg)	TBL1XR1	Likely pathogenic	criteria provided, single submitter
1285415	NM_024665.7(TBL1XR1):c.728G>A (p.Gly243Asp)	TBL1XR1	Likely pathogenic	criteria provided, single submitter
1300134	NM_024665.7(TBL1XR1):c.679G>A (p.Asp227Asn)	TBL1XR1	Likely pathogenic	criteria provided, single submitter
1320238	NM_024665.7(TBL1XR1):c.204+2del	TBL1XR1	Likely pathogenic	criteria provided, single submitter
1679385	NM_024665.7(TBL1XR1):c.59-1G>A	TBL1XR1	Likely pathogenic	criteria provided, single submitter
1686654	NM_024665.7(TBL1XR1):c.187G>A (p.Glu63Lys)	TBL1XR1	Likely pathogenic	criteria provided, single submitter
1804067	NM_024665.7(TBL1XR1):c.524G>A (p.Cys175Tyr)	TBL1XR1	Likely pathogenic	criteria provided, single submitter
191371	NM_024665.7(TBL1XR1):c.209G>A (p.Gly70Asp)	TBL1XR1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
TBL1XR1	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 41	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBL1XR1	Orphanet:487825	Pierpont syndrome
TBL1XR1	Orphanet:520	Acute promyelocytic leukemia

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBL1XR1	HGNC:29529	ENSG00000177565	Q9BZK7	F-box-like/WD repeat-containing protein TBL1XR1	gencc,clinvar
TBL1XR1-AS1	HGNC:41243	ENSG00000231310		TBL1XR1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBL1XR1	F-box-like/WD repeat-containing protein TBL1XR1	F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBL1XR1	Scaffold/PPI	no		WD40_rpt, LisH, WD40/YVTN_repeat-like_dom_sf
TBL1XR1-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
nipple	1
tibia	1
corpus callosum	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBL1XR1	284	ubiquitous	marker	calcaneal tendon, nipple, tibia
TBL1XR1-AS1	117		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBL1XR1	4,066
TBL1XR1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TBL1XR1	Q9BZK7	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 61. Enrichment computed across 2 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
Loss of MECP2 binding ability to the NCoR/SMRT complex	1	1631.4×	0.009	TBL1XR1
Loss of function of MECP2 in Rett syndrome	1	1427.5×	0.009	TBL1XR1
Pervasive developmental disorders	1	1427.5×	0.009	TBL1XR1
Disorders of Developmental Biology	1	1427.5×	0.009	TBL1XR1
Disorders of Nervous System Development	1	1427.5×	0.009	TBL1XR1
R-HSA-1368082	1	713.8×	0.010	TBL1XR1
BMAL1:CLOCK,NPAS2 activates circadian expression	1	423.0×	0.010	TBL1XR1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	407.9×	0.010	TBL1XR1
Signaling by NOTCH1 in Cancer	1	407.9×	0.010	TBL1XR1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	407.9×	0.010	TBL1XR1
Notch-HLH transcription pathway	1	407.9×	0.010	TBL1XR1
RORA,B,C and NR1D1 (REV-ERBA) regulate gene expression	1	407.9×	0.010	TBL1XR1
NR1H2 and NR1H3-mediated signaling	1	393.8×	0.010	TBL1XR1
Regulation of MECP2 expression and activity	1	368.4×	0.010	TBL1XR1
Signaling by NOTCH1	1	356.9×	0.010	TBL1XR1
R-HSA-400253	1	346.1×	0.010	TBL1XR1
HCMV Infection	1	326.3×	0.010	TBL1XR1
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	317.2×	0.010	TBL1XR1
Transcriptional Regulation by MECP2	1	317.2×	0.010	TBL1XR1
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	1	308.6×	0.010	TBL1XR1
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	292.8×	0.010	TBL1XR1
Activation of gene expression by SREBF (SREBP)	1	259.6×	0.011	TBL1XR1
NOTCH1 Intracellular Domain Regulates Transcription	1	237.9×	0.011	TBL1XR1
Heme signaling	1	215.5×	0.011	TBL1XR1
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	215.5×	0.011	TBL1XR1
Transcriptional activation of mitochondrial biogenesis	1	203.9×	0.011	TBL1XR1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.011	TBL1XR1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.011	TBL1XR1
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	196.9×	0.011	TBL1XR1
Cytoprotection by HMOX1	1	184.2×	0.011	TBL1XR1

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
regulation of triglyceride metabolic process	1	2106.5×	0.004	TBL1XR1
fat pad development	1	1685.2×	0.004	TBL1XR1
response to dietary excess	1	1123.5×	0.004	TBL1XR1
white fat cell differentiation	1	842.6×	0.004	TBL1XR1
blastocyst hatching	1	543.6×	0.005	TBL1XR1
lipid catabolic process	1	244.2×	0.010	TBL1XR1
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.013	TBL1XR1
multicellular organism growth	1	137.0×	0.013	TBL1XR1
chromatin organization	1	99.1×	0.016	TBL1XR1
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.027	TBL1XR1
positive regulation of DNA-templated transcription	1	27.9×	0.046	TBL1XR1
negative regulation of transcription by RNA polymerase II	1	17.7×	0.066	TBL1XR1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.072	TBL1XR1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	TBL1XR1

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
TBL1XR1	0	0
TBL1XR1-AS1	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
TBL1XR1	2	Binding:2

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	2	TBL1XR1, TBL1XR1-AS1

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)
TBL1XR1	2	—
TBL1XR1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.