263.4 kb deletion within the TCF4 gene consistent with Pitt-Hopkins syndrome, inherited from a mosaic parent with normal phenotype

Eur J Med Genet. 2013 Jun;56(6):314-8. doi: 10.1016/j.ejmg.2013.03.005. Epub 2013 Mar 23.


Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental genetic disorder, remaining under-diagnosed due to similarities with other known genetic syndromes. It is mainly characterized by severe intellectual disability, overbreathing, a typical facial gestalt, tendency to epilepsy and is caused by TCF4 haploinsufficiency. We report on a 14-year old boy, born to healthy non-consanguineous parents, with a PTHS spectrum phenotype, presenting with moderate to severe developmental delay, severe speech delay and facial dysmorphism. Genetic investigation using array-based comparative genomic hybridization (array-CGH) with a 400K custom array, revealed a 263.4 kb deletion within the TCF4 gene, removing exons 4-9. Parental array-CGH analysis was also performed, indicating paternal mosaicism for the same deletion. The mosaicism was confirmed by Quantitative Real-Time PCR. The current report describes a new TCF4 deletion associated with a PTHS phenotype. Moreover, it is the first case to our knowledge, where such a deletion is shown to be inherited from a clinically unaffected mosaic parent. Our results highlight the importance of parental testing in this setting for more accurate and focused prenatal diagnosis. The level and tissue-specificity of mosaicism in the father would be an interesting direction for further studies.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
  • Chromosome Banding
  • Comparative Genomic Hybridization
  • Facies
  • Female
  • Gene Deletion*
  • Humans
  • Hyperventilation / diagnosis*
  • Hyperventilation / genetics*
  • Intellectual Disability / diagnosis*
  • Intellectual Disability / genetics*
  • Karyotype
  • Male
  • Mosaicism*
  • Phenotype*
  • Transcription Factor 4
  • Transcription Factors / genetics*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • TCF4 protein, human
  • Transcription Factor 4
  • Transcription Factors

Supplementary concepts

  • Pitt-Hopkins syndrome