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

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Abstract

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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Acknowledgements

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

Funding

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

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Authors and Affiliations

  1. Shanghai Engineering Research Center for Big Data in Pediatric Precision Medicine, Center for Biomedical Informatics, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, China

    Tingting Zhao, Georgi Z. Genchev, Guangjun Yu & Hui Lu

  2. Bulgarian Institute for Genomics and Precision Medicine, Sofia, Bulgaria

    Georgi Z. Genchev

  3. SJTU-Yale Joint Center for Biostatistics, Department of Bioinformatics and Biostatistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China

    Georgi Z. Genchev & Hui Lu

  4. Molecular Diagnostic Laboratory, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, China

    Shengnan Wu

  5. Department of Rehabilitation, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, China

    Jincai Feng

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  1. Tingting Zhao
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  2. Georgi Z. Genchev
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  3. Shengnan Wu
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  4. Guangjun Yu
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  5. Hui Lu
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Contributions

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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The authors declare no competing interests.

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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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