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Further delineation of Pitt–Hopkins syndrome: phenotypic and genotypic description of 16 novel patients
  1. C Zweier1,
  2. H Sticht2,
  3. E K Bijlsma3,
  4. J Clayton-Smith4,
  5. S E Boonen5,
  6. A Fryer6,
  7. M T Greally7,
  8. L Hoffmann8,
  9. N S den Hollander3,
  10. M Jongmans9,
  11. S G Kant3,
  12. M D King10,
  13. S A Lynch7,
  14. S McKee11,
  15. A T Midro12,
  16. S-M Park13,
  17. V Ricotti10,
  18. E Tarantino14,
  19. M Wessels15,
  20. M Peippo16,
  21. A Rauch1
  1. 1
    Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
  2. 2
    Bioinformatics, Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
  3. 3
    Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  4. 4
    Academic Department of Medical Genetics and Regional Genetic Services, St Mary’s Hospital, University of Manchester, Manchester, UK
  5. 5
    Kennedy Center, National Research Center for Genetics, Visual Impairment and Mental Retardation, Glostrup, Denmark
  6. 6
    Department of Clinical Genetics, Royal Liverpool Children’s Hospital, Liverpool, UK
  7. 7
    National Centre for Medical Genetics, Our Lady’s Hospital for Sick Children, Crumlin, Dublin, Ireland
  8. 8
    Department of Pediatrics, Naestved Hospital, Naestved, Denmark
  9. 9
    Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
  10. 10
    Department of Pediatric Neurology, Children’s University Hospital, Temple Street, Dublin, Ireland
  11. 11
    Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK
  12. 12
    Department of Clinical Genetics, Medical University Bialystok, Bialystok, Poland
  13. 13
    Department of Clinical Genetics, Addenbrooke’s Hospital, Cambridge, UK
  14. 14
    Section of Clinical Genetics, Department of Pediatrics, S. Chiara Hospital, Pisa, Italy
  15. 15
    Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands
  16. 16
    The Department of Medical Genetics, Väestöliitto, Helsinki, Finland
  1. Dr A Rauch, Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany; arauch{at}


Background: Haploinsufficiency of the gene encoding for transcription factor 4 (TCF4) was recently identified as the underlying cause of Pitt–Hopkins syndrome (PTHS), an underdiagnosed mental-retardation syndrome characterised by a distinct facial gestalt, breathing anomalies and severe mental retardation.

Methods: TCF4 mutational analysis was performed in 117 patients with PTHS-like features.

Results: In total, 16 novel mutations were identified. All of these proven patients were severely mentally retarded and showed a distinct facial gestalt. In addition, 56% had breathing anomalies, 56% had microcephaly, 38% had seizures and 44% had MRI anomalies.

Conclusion: This study provides further evidence of the mutational and clinical spectrum of PTHS and confirms its important role in the differential diagnosis of severe mental retardation.

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  • Competing interests: None.

  • Patient consent: Parental consent obtained.