title: 263.4 kb deletion within the TCF4 gene consistent with Pitt-Hopkins syndrome, inherited from a mosaic parent with normal phenotype.
abstract: 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.
authors.affiliation: The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kousoulidou
authors.forename: George
authors.initials: G
authors.lastname: Tanteles
authors.forename: Maria
authors.initials: M
authors.lastname: Moutafi
authors.forename: Carolina
authors.initials: C
authors.lastname: Sismani
authors.forename: Philippos C
authors.initials: PC
authors.lastname: Patsalis
authors.forename: Violetta
authors.initials: V
authors.lastname: Anastasiadou
mesh_terms: D000293:Adolescent; D000328:Adult; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002871:Chromosome Banding; D055028:Comparative Genomic Hybridization; D019066:Facies; D005260:Female; D017353:Gene Deletion; D006801:Humans; D006985:Hyperventilation / Q000175:diagnosis* / Q000235:genetics*; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D059785:Karyotype; D008297:Male; D009030:Mosaicism; D010641:Phenotype; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors