Impairment of different protein domains causes variable clinical presentation within Pitt-Hopkins syndrome and suggests intragenic molecular syndromology of TCF4

Giuseppe Marangi, Silvia Frangella, Marcella Zollino, Stefania Ricciardi, Daniela Orteschi, Marina Murdolo, Serena Lattante, Maria Francesca Bedeschi, Maria Rosaria Calvello, Marco Baccarin, Silvana Guerneri, Beth Keena, Margaret H. Harr, Elaine Zackai

Risultato della ricerca: Contributo in rivistaArticolo in rivista

8 Citazioni (Scopus)

Abstract

Pitt-Hopkins syndrome is a neurodevelopmental disorder characterized by severe intellectual disability and a distinctive facial gestalt. It is caused by haploinsufficiency of the TCF4 gene. The TCF4 protein has different functional domains, with the NLS (nuclear localization signal) domain coded by exons 7–8 and the bHLH (basic Helix-Loop-Helix) domain coded by exon 18. Several alternatively spliced TCF4 variants have been described, allowing for translation of variable protein isoforms. Typical PTHS patients have impairment of at least the bHLH domain. To which extent impairment of the remaining domains contributes to the final phenotype is not clear. There is recent evidence that certain loss-of-function variants disrupting TCF4 are associated with mild ID, but not with typical PTHS. We describe a frameshift-causing partial gene deletion encompassing exons 4–6 of TCF4 in an adult patient with mild ID and nonspecific facial dysmorphisms but without the typical features of PTHS, and a c.520C > T nonsense variant within exon 8 in a child presenting with a severe phenotype largely mimicking PTHS, but lacking the typical facial dysmorphism. Investigation on mRNA, along with literature review, led us to suggest a preliminary phenotypic map of loss-of-function variants affecting TCF4. An intragenic phenotypic map of loss-of-function variants in TCF4 is suggested here for the first time: variants within exons 1–4 and exons 4–6 give rise to a recurrent phenotype with mild ID not in the spectrum of Pitt-Hopkins syndrome (biallelic preservation of both the NLS and bHLH domains); variants within exons 7–8 cause a severe phenotype resembling PTHS but in absence of the typical facial dysmorphism (impairment limited to the NLS domain); variants within exons 9–19 cause typical Pitt-Hopkins syndrome (impairment of at least the bHLH domain). Understanding the TCF4 molecular syndromology can allow for proper nosology in the current era of whole genomic investigations.
Lingua originaleEnglish
pagine (da-a)565-571
Numero di pagine7
RivistaEuropean Journal of Medical Genetics
Volume60
DOI
Stato di pubblicazionePubblicato - 2017

Keywords

  • Alternative Splicing
  • Child
  • Codon, Nonsense
  • Facies
  • Female
  • Frameshift Mutation
  • Genetics
  • Genetics (clinical)
  • Humans
  • Hyperventilation
  • Intellectual Disability
  • Loss of Function Mutation
  • Male
  • Middle Aged
  • NLS domain
  • Phenotype
  • Pitt-Hopkins syndrome
  • Protein Domains
  • TCF4
  • Transcription Factor 4
  • bHLH domain

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