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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described. [provided by RefSeq, Jul 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

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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ClinVar Variants

300 unique Pathogenic / Likely Pathogenic· 438 VUS of 1288 total submissions

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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 →

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GeneReview available — TCF4

Authoritative clinical overview · Recommended first read

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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 OE?0.09 (0.05–0.22)

0≤0.351.4

Missense OE?0.44 (0.39–0.50)

0≤0.61.4

Synonymous OE?0.97

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

This gene — mechanism propensity

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 · 71% of P/LP variants are LoF · LOEUF 0.22 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.1

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.2

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

References

ClinVar Variant Classifications

1288 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic192

Likely Pathogenic108

VUS438

Likely Benign401

Benign109

Conflicting20

192

Pathogenic

108

Likely Pathogenic

438

VUS

401

Likely Benign

109

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	152	21	18	1	192
Likely Pathogenic	60	43	5	0	108
VUS	10	314	107	7	438
Likely Benign	3	48	176	174	401
Benign	0	16	87	6	109
Conflicting	—				20
Total	225	442	393	188	1,268

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

82 pathogenic / likely-pathogenic (of 93) ClinVar copy-number / structural variants overlap TCF4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →