Pitt–Hopkins syndrome: phenotypic and genotypic description of four unrelated patients and structural analysis of corresponding missense mutations


Pitt–Hopkins syndrome is an underdiagnosed neurodevelopmental disorder which is characterized by specific facial features, early-onset developmental delay, and moderate to severe intellectual disability. The genetic cause, a deficiency of the TCF4 gene, has been established; however, the underlying pathological mechanisms of this disease are still unclear. Herein, we report four unrelated children with different de novo mutations (T606A, K607E, R578C, and V617I) located at highly conserved sites and with clinical phenotypes which present variable degrees of developmental delay and intellectual disability. Three of these four missense mutations have not yet been reported. The patient with V617I mutation exhibits mild intellectual disability and has attained more advanced motor and verbal skills, which is significantly different from other cases reported to date. Molecular dynamics simulations are used to explore the atomic level mechanism of how missense mutations impair the functions of TCF4. Mutations T606A, K607E, and R578C are found to affect DNA binding directly or indirectly, while V617I only induces subtle conformational changes, which is consistent with the milder clinical phenotype of the corresponding patient. The study expands the mutation spectrum and phenotypic characteristics of Pitt–Hopkins syndrome, and reinforces the genotype–phenotype correlation and strengthens the understanding of phenotype variability, which is helpful for further investigation of pathogenetic mechanisms and improved genetic counseling.

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We wish to thank the patients and their families for their participation in this study.


This research was funded by Shanghai Municipal Commission of Health and Family Planning (Grant No. 2018ZHYL0223).

Author information




Conceptualization, J.F.; methodology, J.F. and H.L.; software, T.Z. and G.Z.G.; validation, T.Z. and G.Z.G.; formal analysis, J.F., T.Z., and G.Z.G.; investigation, J.F., T.Z., and G.Z.G.; writing—original draft preparation, T.Z. and G.Z.G.; writing—review and editing, J.F., H.L., and S.W.; visualization, T.Z. and G.Z.G.; supervision, J.F. and G.Y.; project administration, J.F. and T.Z.; funding acquisition, G.Y. All the authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Hui Lu or Jincai Feng.

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The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethical Committee of Children’s Hospital of Shanghai and informed consent was obtained from all the patients.

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Zhao, T., Genchev, G.Z., Wu, S. et al. Pitt–Hopkins syndrome: phenotypic and genotypic description of four unrelated patients and structural analysis of corresponding missense mutations. Neurogenetics 22, 161–169 (2021). https://doi.org/10.1007/s10048-021-00651-8

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  • Pitt–Hopkins syndrome
  • TCF4
  • Missense mutations
  • Phenotypic diversity
  • Molecular dynamics simulation