TCF7L2-related neurodevelopmental disorder

Summary

TCF7L2-related neurodevelopmental disorder (MONDO:0100525) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	TCF7L2-related neurodevelopmental disorder
Mondo ID	MONDO:0100525
Is cancer (heuristic)	no

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › TCF7L2-related neurodevelopmental disorder

Related subtypes (20): intellectual disability, microcephaly, Williams syndrome, Aicardi syndrome, Hao-Fountain syndrome, toluene embryopathy, alternating hemiplegia, atypical Rett syndrome, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, complex neurodevelopmental disorder, Mendelian neurodevelopmental disorder, neurodevelopmental disorder with seizures and brain abnormalities, Yoon-Bellen neurodevelopmental syndrome, neurodevelopmental disorder with microcephaly, hypotonia, and absent language, neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss, neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, neurodevelopmental disorder with parkinsonism or other movement abnormalities, neurodevelopmental disorder with seizures and impaired intellectual and language development, Ebstein-Bezieau neurodevelopmental syndrome, Luo-Agrawal neurodevelopmental syndrome

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3383533	NM_001367943.1(TCF7L2):c.1258C>T (p.Arg420Trp)	TCF7L2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4813341	NM_001367943.1(TCF7L2):c.553-3538_685+1239del	TCF7L2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCF7L2	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
TCF7L2	HGNC:11641	ENSG00000148737	Q9NQB0	Transcription factor 7-like 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TCF7L2	Transcription factor 7-like 2	Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCF7L2	Other/Unknown	no		HMG_box_dom, CTNNB1-bd_N, TCF/LEF

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
endothelial cell	1
lateral nuclear group of thalamus	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCF7L2	291	ubiquitous	marker	lateral nuclear group of thalamus, endothelial cell, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TCF7L2	3,775

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TCF7L2	Q9NQB0	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. 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
Signaling by TCF7L2 mutants	1	2855.0×	0.007	TCF7L2
Binding of TCF/LEF:CTNNB1 to target gene promoters	1	1142.0×	0.007	TCF7L2
RUNX3 regulates WNT signaling	1	1142.0×	0.007	TCF7L2
Incretin synthesis, secretion, and inactivation	1	1038.2×	0.007	TCF7L2
Repression of WNT target genes	1	713.8×	0.007	TCF7L2
Formation of definitive endoderm	1	713.8×	0.007	TCF7L2
Signaling by WNT in cancer	1	601.0×	0.007	TCF7L2
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	571.0×	0.007	TCF7L2
Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	1	519.1×	0.007	TCF7L2
Beta-catenin independent WNT signaling	1	292.8×	0.009	TCF7L2
Peptide hormone metabolism	1	271.9×	0.009	TCF7L2
Transcriptional regulation by RUNX3	1	271.9×	0.009	TCF7L2
Transcriptional Regulation by VENTX	1	265.6×	0.009	TCF7L2
Gastrulation	1	259.6×	0.009	TCF7L2
Deactivation of the beta-catenin transactivating complex	1	233.1×	0.009	TCF7L2
MITF-M-dependent gene expression	1	181.3×	0.010	TCF7L2
Ca2+ pathway	1	178.4×	0.010	TCF7L2
Degradation of beta-catenin by the destruction complex	1	173.0×	0.010	TCF7L2
Formation of the beta-catenin:TCF transactivating complex	1	120.2×	0.012	TCF7L2
TCF dependent signaling in response to WNT	1	117.7×	0.012	TCF7L2
MITF-M-regulated melanocyte development	1	114.2×	0.012	TCF7L2
Signaling by WNT	1	112.0×	0.012	TCF7L2
Regulation of PD-L1(CD274) transcription	1	108.8×	0.012	TCF7L2
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.023	TCF7L2
RNA Polymerase II Transcription	1	22.5×	0.055	TCF7L2
Gene expression (Transcription)	1	17.8×	0.067	TCF7L2
Generic Transcription Pathway	1	15.1×	0.076	TCF7L2
Developmental Biology	1	14.5×	0.077	TCF7L2
Disease	1	13.1×	0.082	TCF7L2
Metabolism of proteins	1	12.4×	0.084	TCF7L2

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
positive regulation of heparan sulfate proteoglycan biosynthetic process	1	4213.0×	0.002	TCF7L2
regulation of hormone metabolic process	1	3370.4×	0.002	TCF7L2
maintenance of DNA repeat elements	1	3370.4×	0.002	TCF7L2
myoblast fate commitment	1	3370.4×	0.002	TCF7L2
negative regulation of type B pancreatic cell apoptotic process	1	2106.5×	0.002	TCF7L2
regulation of smooth muscle cell proliferation	1	1296.3×	0.003	TCF7L2
negative regulation of androgen receptor signaling pathway	1	936.2×	0.004	TCF7L2
negative regulation of gluconeogenesis	1	802.5×	0.004	TCF7L2
pancreas development	1	674.1×	0.004	TCF7L2
negative regulation of extrinsic apoptotic signaling pathway	1	421.3×	0.006	TCF7L2
positive regulation of protein localization to nucleus	1	391.9×	0.006	TCF7L2
blood vessel development	1	374.5×	0.006	TCF7L2
positive regulation of epithelial to mesenchymal transition	1	318.0×	0.006	TCF7L2
response to glucose	1	255.3×	0.006	TCF7L2
positive regulation of insulin secretion	1	255.3×	0.006	TCF7L2
positive regulation of epithelial cell proliferation	1	244.2×	0.006	TCF7L2
fat cell differentiation	1	181.2×	0.008	TCF7L2
canonical Wnt signaling pathway	1	153.2×	0.009	TCF7L2
glucose homeostasis	1	130.6×	0.010	TCF7L2
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.011	TCF7L2
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	78.4×	0.015	TCF7L2
negative regulation of DNA-templated transcription	1	31.6×	0.036	TCF7L2
negative regulation of transcription by RNA polymerase II	1	17.7×	0.061	TCF7L2
positive regulation of transcription by RNA polymerase II	1	14.9×	0.070	TCF7L2
regulation of transcription by RNA polymerase II	1	11.7×	0.086	TCF7L2

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
TCF7L2	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
TCF7L2	22	Binding:22

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	TCF7L2

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)
TCF7L2	22	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.