title: Mosaic 18q21.2 deletions including the TCF4 gene: a clinical report.
abstract: Pitt-Hopkins syndrome (PTHS) is characterized by distinctive facial dysmorphism, profound intellectual disability, and the possible occurrence of epilepsy and breathing anomalies. It is caused by haploinsufficiency of the TCF4 gene. No significant difference in clinical severity has been reported to date between PTHS patients carrying 18q21 deletions including the TCF4 gene, and those harboring TCF4 point mutations, suggesting a lack of genotype/phenotype correlation. Moreover, the size of 18q21 deletions including the TCF4 gene does not appear to have a significant effect on the phenotypic severity, suggesting that TCF4 haploinsufficiency is the most important prognostic factor in 18q deletions. We describe two unrelated patients presenting with clinical features reminiscent of PTHS and carrying mosaic interstitial 18q21 deletions characterized by array comparative genomic hybridization. One of the patients presented the lowest level of mosaic 18q21 deletion reported to date (5-10%). Our report and a review of the literature show that the mosaic status does not appear to have a significant effect on the clinical severity of 18q21 deletions, which are associated with a poor neurological outcome, whereas a mosaic TCF4 point mutation can result in a significantly milder phenotype. Malformations of internal organs are currently considered to be rare in PTHS. The patients described here had visceral anomalies, suggesting that a full morphological assessment, including heart and abdominal ultrasound scans, should be performed systematically in PTHS patients.
authors.affiliation: Centre de référence des anomalies du développement, Service de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, Bron, France. massimiliano.rossi01@chu-lyon.fr
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Rossi
authors.forename: Audrey
authors.initials: A
authors.lastname: Labalme
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Cordier
authors.forename: Marianne
authors.initials: M
authors.lastname: Till
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Blanchard
authors.forename: Remi
authors.initials: R
authors.lastname: Dubois
authors.forename: Laurent
authors.initials: L
authors.lastname: Guibaud
authors.forename: Sophie
authors.initials: S
authors.lastname: Heissat
authors.forename: Etienne
authors.initials: E
authors.lastname: Javouhey
authors.forename: Alain
authors.initials: A
authors.lastname: Lachaux
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Mure
authors.forename: Dorothée
authors.initials: D
authors.lastname: Ville
authors.forename: Patrick
authors.initials: P
authors.lastname: Edery
authors.forename: Damien
authors.initials: D
authors.lastname: Sanlaville
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18; D019066:Facies; D005260:Female; D006801:Humans; D006985:Hyperventilation / Q000235:genetics*; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D017384:Sequence Deletion; 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