TCF4

Chr 18AD

transcription factor 4

Also known as: CDG2T, E2-2, FCD2, FECD3, ITF-2, ITF2, PTHS, SEF-2

NCBI Gene: 6925 ENSG00000196628 UniProt: P15884 OMIM: 602272

The encoded transcription factor recognizes E-box binding sites and is broadly expressed with important roles in nervous system development. Mutations cause Pitt-Hopkins syndrome through loss of function, while intronic CTG repeat expansions (>50 units) cause Fuchs endothelial corneal dystrophy. Both conditions follow autosomal dominant inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismADLOEUF 0.222 OMIM phenotypes

VCEP Guidelines: Rett/Angelman-like DisordersPilot

View Specifications ClinGen Panel

Clinical Summary— TCF4

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Gene-Disease Validity (ClinGen)

Pitt-Hopkins syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.22LOEUF

pLI 1.000

Z-score 5.44

OE 0.09 (0.05–0.22)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

4.10Z-score

OE missense 0.44 (0.39–0.50)

187 obs / 425.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.09 (0.05–0.22)

0≤0.351.4

Missense OE0.44 (0.39–0.50)

0≤0.61.4

Synonymous OE0.97

0≤1.21.6

LoF obs/exp: 4 / 42.1Missense obs/exp: 187 / 425.1Syn Z: 0.28

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTCF4-related Pitt-Hopkins syndromeLOFAD

strongTCF4-related corneal dystrophy, fuchs endothelialOTHERAD

0.3594th %ile

GOF

0.1899th %ile

LOF

0.91top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.22

DN1 literature citation

Literature Evidence

DNPitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects.PMID:22460224

LOFRESULTS: We here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans.PMID:33228529

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.