TCF4 – Autism Spectrum Disorder

Autosomal dominant haploinsufficiency of TCF4 underlies Pitt–Hopkins syndrome (PTHS), a syndromic form of autism spectrum disorder characterized by severe developmental delay, intellectual disability, and distinctive facial features. Patient‐specific induced pluripotent stem cells (iPSCs) generated from 5 unrelated PTHS individuals all harbor heterozygous TCF4 mutations and exhibit impaired neurodevelopmental differentiation, confirming a direct link between TCF4 loss‐of‐function and ASD-like cellular phenotypes (PMID:32971458).

In a cohort of 250 Vietnamese children with non‐syndromic ASD, a pathogenic nonsense variant c.469C>T (p.Arg157Ter) in TCF4 was identified among 23 validated pathogenic or likely pathogenic mutations across multiple ASD‐associated genes, supporting a broader role for TCF4 truncating alleles in ASD (PMID:38287090).

All reported ASD‐associated TCF4 variants are heterozygous loss‐of‐function alleles arising de novo or inherited in an autosomal dominant manner. No extended familial segregation has been documented, consistent with the high rate of de novo events in PTHS and related disorders.

Functional studies in multiple mouse models of Tcf4 haploinsufficiency recapitulate core neurobehavioral and synaptic hallmarks of ASD, including microcephaly, hyperactivity, reduced anxiety, and exaggerated hippocampal long‐term potentiation driven by NMDA receptor hyperfunction (PMID:29222403).

Cell‐type specific profiling in PTHS mouse lines reveals selective reduction of parvalbumin‐positive, vasoactive intestinal peptide–positive, and cortistatin‐positive GABAergic interneurons, leading to imbalanced excitatory–inhibitory circuitry—a key feature of ASD pathophysiology (PMID:37770578).

Collectively, heterozygous LoF mutations in TCF4 confer moderate clinical validity for ASD through consistent de novo truncating variants in syndromic and non‐syndromic cases, supported by concordant functional data in cellular and animal models. Further segregation studies and genotype–phenotype correlations will refine risk assessment. Key take-home: TCF4 haploinsufficiency disrupts interneuron development and synaptic balance, representing a clinically actionable mechanism in ASD.

References

• Stem cell research • 2020 • Generation of 10 patient-specific induced pluripotent stem cells (iPSCs) to model Pitt-Hopkins Syndrome. PMID:32971458
• Journal Unknown • 2023 • Genome-wide SNP genotyping identifies TCF4 truncating mutation in ASD PMID:38287090
• The Journal of Neuroscience • 2018 • Common Pathophysiology in Multiple Mouse Models of Pitt-Hopkins Syndrome. PMID:29222403
• Molecular Psychiatry • 2023 • Psychiatric risk gene Transcription Factor 4 (TCF4) regulates the density and connectivity of distinct inhibitory interneuron subtypes. PMID:37770578

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