Molecular Mechanisms of Transcription Factor 4 in Pitt-Hopkins Syndrome


Purpose of Review

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder that results from mutations of the clinically pleiotropic transcription factor 4 (TCF4) gene. Mutations in the genomic locus of TCF4 on chromosome 18 have been linked to multiple disorders including 18q syndrome, schizophrenia, Fuch’s corneal dystrophy, and sclerosing cholangitis. For PTHS, TCF4 mutation or deletion leads to the production of a dominant negative TCF4 protein and/or haploinsufficiency that result in abnormal brain development. The biology of TCF4 has been studied for several years in regard to its role in immune cell differentiation, although its role in neurodevelopment and the mechanisms resulting in the severe symptoms of PTHS are not well studied.

Recent Findings

Here, we summarize the current understanding of PTHS and recent findings that have begun to describe the biological implications of TCF4 deficiency during brain development and into adulthood. In particular, we focus on recent work that has looked at the role of TCF4 biology within the context of PTHS and highlight the potential for identification of therapeutic targets for PTHS.


PTHS research continues to uncover mutations in TCF4 that underlie the genetic cause of this rare disease, and emerging evidence for molecular mechanisms that TCF4 regulates in brain development and neuronal function is contributing to a more complete picture of how pathology arises from this genetic basis, with important implications for the potential of future clinical care.

This is a preview of subscription content, log in to check access.


Papers of particular interest, published recently, have been highlighted as : • Of importance

  1. 1.

    Amiel J, Rio M, de Pontual L, et al. Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. Am J Hum Genet. 2007;80:988–93.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Brockschmidt A, Filippi A, Charbel Issa P, et al. Neurologic and ocular phenotype in Pitt-Hopkins syndrome and a zebrafish model. Hum Genet. 2011;130:645–55.

    Article  PubMed  Google Scholar 

  3. 3.

    Zweier C, Sticht H, Bijlsma EK, et al. Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients. J Med Genet. 2008;45:738–44.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    • Sepp M, Pruunsild P, Timmusk T. Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects. Hum Mol Genet. 2012;21:2873–88. Description of PTHS-related mutations in relation to resulting TCF4 function. Evidence of a range of mutation impact from subtle deficiencies to dominant-negative effects

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Whalen S, Héron D, Gaillon T, et al. Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum. Hum Mutat. 2012;33:64–72.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Grant SFA, Thorleifsson G, Reynisdottir I, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006;38:320–3.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Forrest MP, Hill MJ, Quantock AJ, et al. The emerging roles of TCF4 in disease and development. Trends Mol Med. 2014;20:322–31.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Sweatt JD. Pitt-Hopkins syndrome: intellectual disability due to loss of TCF4-regulated gene transcription. Exp Mol Med. 2013;45:e21.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Pitt D, Hopkins I. A syndrome of mental retardation, wide mouth and intermittent overbreathing. Aust Paediatr J. 1978;14:182–4.

    CAS  PubMed  Google Scholar 

  10. 10.

    Marangi G, Ricciardi S, Orteschi D, et al. Proposal of a clinical score for the molecular test for Pitt-Hopkins syndrome. Am J Med Genet A. 2012;158A:1604–11.

    Article  PubMed  Google Scholar 

  11. 11.

    Van Balkom IDC, Vuijk PJ, Franssens M, et al. Development, cognition, and behaviour in Pitt-Hopkins syndrome. Dev Med Child Neurol. 2012;54:925–31.

    Article  PubMed  Google Scholar 

  12. 12.

    de Pontual L, Mathieu Y, Golzio C, et al. Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. Hum Mutat. 2009;30:669–76.

    Article  PubMed  Google Scholar 

  13. 13.

    Marangi G, Ricciardi S, Orteschi D, et al. The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria. Am J Med Genet A. 2011;155A:1536–45.

    Article  PubMed  Google Scholar 

  14. 14.

    Soileau B, Hasi M, Sebold C, et al. Adults with chromosome 18 abnormalities. J Genet Couns. 2015;24:663–74.

    Article  PubMed  Google Scholar 

  15. 15.

    Forrest M, Chapman RM, Doyle AM, et al. Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome. Hum Mutat. 2012;33:1676–86.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Zweier C, Peippo MM, Hoyer J, et al. Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome). Am J Hum Genet. 2007;80:994–1001.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Brockschmidt A, Todt U, Ryu S, et al. Severe mental retardation with breathing abnormalities (Pitt–Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4. Hum Mol Genet. 2007;16:1488–94.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Rannals MD, Page SC, Campbell MN, et al. Neurodevelopmental models of transcription factor 4 deficiency converge on a common ion channel as a potential therapeutic target for Pitt Hopkins syndrome. Rare Diseases. 2016;4:e1220468.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Rosenfeld JA, Leppig K, Ballif BC, et al. Genotype–phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. Genet Med. 2009;11:797–805.

    Article  PubMed  Google Scholar 

  20. 20.

    Maini I, Cantalupo G, Turco EC, et al. Clinical and polygraphic improvement of breathing abnormalities after valproate in a case of Pitt-Hopkins syndrome. J Child Neurol. 2012;27:1585–8.

    Article  PubMed  Google Scholar 

  21. 21.

    Verhulst SL, De Dooy J, Ramet J, et al. Acetazolamide for severe apnea in Pitt-Hopkins syndrome. Am J Med Genet A. 2012;158A:932–4.

    Article  PubMed  Google Scholar 

  22. 22.

    Swenson ER, Leatham KL, Roach RC, et al. Renal carbonic anhydrase inhibition reduces high altitude sleep periodic breathing. Respir Physiol. 1991;86:333–43.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    De Backer WA. Central sleep apnoea, pathogenesis and treatment: an overview and perspective. Eur Respir J. 1995;8:1372–83.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Henthorn P, Kiledjian M, Kadesch T. Two distinct transcription factors that bind the immunoglobulin enhancer uE5/kE2 motif. Science. 1990;247:467–70.

  25. 25.

    Sepp M, Kannike K, Eesmaa A, et al. Functional diversity of human basic helix-loop-helix transcription factor TCF4 isoforms generated by alternative 5′ exon usage and splicing. PLoS One. 2011;6:e22138.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Blake DJ, Forrest M, Chapman RM, et al. TCF4, schizophrenia, and Pitt-Hopkins syndrome. Schizophr Bull. 2010;36:443–7.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Goldfarb AN, Lewandowska K, Pennell CA. Identification of a highly conserved module in E proteins required for in vivo helix-loop-helix dimerization. J Biol Chem. 1998;273:2866–73.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Massari ME, Grant PA, Pray-Grant MG, et al. A conserved motif present in a class of helix-loop-helix proteins activates transcription by direct recruitment of the SAGA complex. Mol Cell. 1999;4:63–73.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Powell LM, Jarman AP. Context dependence of proneural bHLH proteins. Curr Opin Genet Dev. 2008;18:411–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Petropoulos H, Skerjanc IS. Analysis of the inhibition of MyoD activity by ITF-2B and full-length E12/E47. J Biol Chem. 2000;275:25095–101.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Furumura M. Involvement of ITF2 in the transcriptional regulation of melanogenic genes. J Biol Chem. 2001;276:28147–54.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Lu Y, Sheng D-Q, Mo Z-C, et al. A negative regulatory element-dependent inhibitory role of ITF2B on IL-2 receptor α gene. Biochem Biophys Res Commun. 2005;336:142–9.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    • Rannals MD, Hamersky GR, Page SC, et al. Psychiatric risk gene transcription factor 4 regulates intrinsic excitability of prefrontal neurons via repression of SCN10a and KCNQ1. Neuron. 2016;90:43–55. First report of TCF4 directly regulating neuronal excitability. Haploinsufficiency of TCF4 results in the loss of repression of the ion channel gene SCN10a which becomes ectopically expressed and represents a potential therapeutic target

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Hauser J, Sveshnikova N, Wallenius A, et al. B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins. Proc Natl Acad Sci U S A. 2008;105:1267–72.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Hauser J, Saarikettu J, Grundström T. Calcium regulation of myogenesis by differential calmodulin inhibition of basic helix-loop-helix transcription factors. Mol Biol Cell. 2008;19:2509–19.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Hauser J, Wallenius A, Sveshnikova N, et al. Calmodulin inhibition of E2A stops expression of surrogate light chains of the pre-B-cell receptor and CD19. Mol Immunol. 2010;47:1031–8.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Hermann S, Saarikettu J, Onions J, et al. Calcium regulation of basic helix-loop-helix transcription factors. Cell Calcium. 1998;23:135–42.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Corneliussen B, Holm M, Waltersson Y, et al. Calcium/calmodulin inhibition of basic-helix-loop-helix transcription factor domains. Nature. 1994;368:760–4.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Onions J, Hermann S, Grundström T. Basic helix-loop-helix protein sequences determining differential inhibition by calmodulin and S-100 proteins. J Biol Chem. 1997;272:23930–7.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Larsson G, Schleucher J, Onions, et al. A novel target recognition revealed by calmodulin in complex with basic helix–loop–helix transcription factor SEF2–1/E2–2. Protein Sci. 2001;10:169–86.

  41. 41.

    Larsson G, Schleucher J, Onions J, et al. Backbone dynamics of a symmetric calmodulin dimer in complex with the calmodulin-binding domain of the basic-helix-loop-helix transcription factor SEF2-1/E2-2: a highly dynamic complex. Biophys J. 2005;89:1214–26.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Zhang LI, Poo MM. Electrical activity and development of neural circuits. Nat Neurosci. 2001;4(Suppl):1207–14.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Spitzer NC. Electrical activity in early neuronal development. Nature. 2006;444:707–12.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Cancedda L, Fiumelli H, Chen K, Poo M-M. Excitatory GABA action is essential for morphological maturation of cortical neurons in vivo. J Neurosci. 2007;27:5224–35.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Luhmann HJ, Fukuda A, Kilb W. Control of cortical neuronal migration by glutamate and GABA. Front Cell Neurosci. 2015;9:4.

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Komuro H, Rakic P. Orchestration of neuronal migration by activity of ion channels, neurotransmitter receptors, and intracellular Ca2+ fluctuations. J Neurobiol. 1998;37:110–30.

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Hubel DH, Wiesel TN, LeVay S. Plasticity of ocular dominance columns in monkey striate cortex. Philos Trans R Soc Lond Ser B Biol Sci. 1977;278:377–409.

    CAS  Article  Google Scholar 

  48. 48.

    Kleinschmidt A, Bear MF, Singer W. Blockade of “NMDA” receptors disrupts experience-dependent plasticity of kitten striate cortex. Science. 1987;238:355–8.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Shatz CJ. Impulse activity and the patterning of connections during CNS development. Neuron. 1990;5:745–56.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Katz LC, Shatz CJ. Synaptic activity and the construction of cortical circuits. Science. 1996;274:1133–8.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Konur S, Ghosh A. Calcium signaling and the control of dendritic development. Neuron. 2005;46:401–5.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Rosenberg SS, Spitzer NC. Calcium signaling in neuronal development. Cold Spring Harb Perspect Biol. 2011;3:a004259.

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Uhlén P, Fritz N, Smedler E, et al. Calcium signaling in neocortical development. Dev Neurobiol. 2015;75:360–8.

    Article  PubMed  Google Scholar 

  54. 54.

    Ross SE, Greenberg ME, Stiles CD. Basic helix-loop-helix factors in cortical development. Neuron. 2003;39:13–25.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Zhuang Y, Cheng P, Weintraub H. B-lymphocyte development is regulated by the combined dosage of three basic helix-loop-helix genes, E2A, E2-2, and HEB. Mol Cell Biol. 1996;16:2898–905.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Flora A, Garcia JJ, Thaller C, Zoghbi HY. The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors. Proc Natl Acad Sci U S A. 2007;104:15382–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Huang W-H, Tupal S, Huang T-W, et al. Atoh1 governs the migration of postmitotic neurons that shape respiratory effectiveness at birth and chemoresponsiveness in adulthood. Neuron. 2012;75:799–809.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Rose MF, Ren J, Ahmad KA, et al. Math1 is essential for the development of hindbrain neurons critical for perinatal breathing. Neuron. 2009;64:341–54.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Tupal S, Huang W-H, Picardo MCD, et al. Atoh1-dependent rhombic lip neurons are required for temporal delay between independent respiratory oscillators in embryonic mice. Elife. 2014;3:e02265.

    Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    • Kennedy AJ, Rahn EJ, Paulukaitis BS, et al. Tcf4 regulates synaptic plasticity, DNA methylation, and memory function. CellReports. doi:10.1016/j.celrep.2016.08.004. Evidence that HDAC inhibitors can alleviate learning and memory deficits in a PTHS mouse model. Also provides a thorough description of behavioral phenotypes that mirror other ASD mouse models

  61. 61.

    Crawley JN. Designing mouse behavioral tasks relevant to autistic-like behaviors. Ment Retard Dev Disabil Res Rev. 2004;10:248–58.

  62. 62.

    Roullet FI, Crawley JN. Mouse models of autism: testing hypotheses about molecular mechanisms. In: Hagan JJ, editor. Molecular and functional models in neuropsychiatry. Berlin Heidelberg: Springer; 2011. p. 187–212.

    Google Scholar 

  63. 63.

    Crawley JN. Translational animal models of autism and neurodevelopmental disorders. Dialogues Clin Neurosci. 2012;14:293–305.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Grubišić V, Kennedy AJ, Sweatt JD, Parpura V. Pitt-Hopkins mouse model has altered particular gastrointestinal transits in vivo. Autism Res. 2015;8:629–33.

    Article  PubMed  Google Scholar 

  65. 65.

    Goldberg TE, Weinberger DR. Probing prefrontal function in schizophrenia with neuropsychological paradigms. Schizophr Bull. 1988;14:179–83.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Vijayaragavan K, O’Leary ME (2001) Gating properties of Nav1. 7 and Nav1. 8 peripheral nerve sodium channels. Journal of Neuroscience

  67. 67.

    Blair NT, Bean BP. Role of tetrodotoxin-resistant Na+ current slow inactivation in adaptation of action potential firing in small-diameter dorsal root ganglion neurons. J Neurosci. 2003;23:10338–50.

    CAS  PubMed  Google Scholar 

  68. 68.

    • D’Rozario M, Zhang T, Waddell EA, et al. Type I bHLH proteins daughterless and Tcf4 restrict neurite branching and synapse formation by repressing Neurexin in postmitotic neurons. Cell Rep. 2016;15:386–97. Description of TCF4 playing a role in postmitotic neuronal function. Functional expression of TCF4 in postmitotic neurons restricts neurite branching and regulates synapse number

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Zweier C, de Jong EK, Zweier M, et al. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in drosophila. Am J Hum Genet. 2009;85:655–66.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43:969–76.

    Article  Google Scholar 

  71. 71.

    Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

    Article  PubMed Central  Google Scholar 

  72. 72.

    Ripke S, O’Dushlaine C, Chambert K, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45:1150–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Quednow BB, Ettinger U, Mössner R, et al. The schizophrenia risk allele C of the TCF4 rs9960767 polymorphism disrupts sensorimotor gating in schizophrenia spectrum and healthy volunteers. J Neurosci. 2011;31:6684–91.

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Zhu X, Gu H, Liu Z, et al. Associations between TCF4 gene polymorphism and cognitive functions in schizophrenia patients and healthy controls. Neuropsychopharmacology. 2013;38:683–9.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Hui L, Rao W-W, Yu Q, et al. TCF4 gene polymorphism is associated with cognition in patients with schizophrenia and healthy controls. J Psychiatr Res. 2015;69:95–101.

    Article  PubMed  Google Scholar 

  76. 76.

    Talkowski ME, Rosenfeld JA, Blumenthal I, et al. Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell. 2012;149:525–37.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Ye T, Lipska BK, Tao R, et al. Analysis of copy number variations in brain DNA from patients with schizophrenia and other psychiatric disorders. Biol Psychiatry. 2012;72:651–4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Mullegama SV, Alaimo JT, Chen L, Elsea SH. Phenotypic and molecular convergence of 2q23.1 deletion syndrome with other neurodevelopmental syndromes associated with autism spectrum disorder. Int J Mol Sci. 2015;16:7627–43.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Maduro V, Pusey BN, Cherukuri PF, et al. Complex translocation disrupting TCF4 and altering TCF4 isoform expression segregates as mild autosomal dominant intellectual disability. Orphanet J Rare Dis. 2016;11:62.

    Article  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Kalscheuer VM, Feenstra I, Van Ravenswaaij-Arts CMA, et al. Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt–Hopkins syndrome. Am J Med Genet. 2008;146A:2053–9.

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Kharbanda M, Kannike K, Lampe A, et al. Partial deletion of TCF4 in three generation family with non-syndromic intellectual disability, without features of Pitt-Hopkins syndrome. Eur J Med Genet. 2016;59:310–4.

    Article  PubMed  Google Scholar 

  82. 82.

    Hamdan FF, Daoud H, Patry L, et al. Parent-child exome sequencing identifies a de novo truncating mutation in TCF4 in non-syndromic intellectual disability. Clin Genet. 2013;83:198–200.

  83. 83.

    Rauch A, Wieczorek D, Graf E, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380:1674–82.

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    de la Torre-Ubieta L, Won H, Stein JL, Geschwind DH. Advancing the understanding of autism disease mechanisms through genetics. Nat Med. 2016;22:345–61.

    Article  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Mullins C, Fishell G, Tsien RW. Unifying views of autism spectrum disorders: a consideration of autoregulatory feedback loops. Neuron. 2016;89:1131–56.

    CAS  Article  PubMed  Google Scholar 

Download references


This work was supported by NIH grant (R56MH104593) and Pitt-Hopkins Research Foundation Award to B.J.M.

Author information



Corresponding author

Correspondence to Matthew D. Rannals.

Ethics declarations

Conflict of Interest

Matthew D. Rannals declares that he has no conflict of interest.

Brady J. Maher reports grants from the NIH/NIMH during the conduct of study. He reports employment at the Lieber Institute for Brain Development and grants from NIMH outside of the submitted work.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Neurogenetics and Psychiatric Genetics

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rannals, M.D., Maher, B.J. Molecular Mechanisms of Transcription Factor 4 in Pitt-Hopkins Syndrome. Curr Genet Med Rep 5, 1–7 (2017).

Download citation


  • Pitt-Hopkins syndrome
  • Transcription factor 4
  • TCF4
  • ITF2
  • SEF2
  • E2-2
  • Autism spectrum