title: Evidence that homozygous PTPRD gene microdeletion causes trigonocephaly, hearing loss, and intellectual disability.
abstract: BACKGROUND
  The premature fusion of metopic sutures results in the clinical phenotype of trigonocephaly. An association of this characteristic with the monosomy 9p syndrome is well established and the receptor-type protein tyrosine phosphatase gene (PTPRD), located in the 9p24.1p23 region and encoding a major component of the excitatory and inhibitory synaptic organization, is considered as a good candidate to be responsible for this form of craniosynostosis. Moreover PTPRD is known to recruit multiple postsynaptic partners such as IL1RAPL1 which gene alterations lead to non syndromic intellectual disability (ID).
  
  
  RESULTS
  We describe a 30 month old boy with severe intellectual disability, trigonocephaly and dysmorphic facial features such as a midface hypoplasia, a flat nose, a depressed nasal bridge, hypertelorism, a long philtrum and a drooping mouth. Microarray chromosomal analysis revealed the presence of a homozygous deletion involving the PTPRD gene, located on chromosome 9p22.3. Reverse Transcription PCR (RT-PCR) amplifications all along the gene failed to amplify the patient's cDNA in fibroblasts, indicating the presence of two null PTPRD alleles. Synaptic PTPRD interacts with IL1RAPL1 which defects have been associated with intellectual disability (ID) and autism spectrum disorder. The absence of the PTPRD transcript leads to a decrease in the expression of IL1RAPL1. These results suggest the direct involvement of PTPRD in ID, which is consistent with the PTPRD -/- mice phenotype. Deletions of PTPRD have been previously suggested as a cause of trigonocephaly in patients with monosomy 9p and genome-wide association study suggested variations in PTPRD are associated with hearing loss.
  
  
  CONCLUSIONS
  The deletion identified in the reported patient supports previous hypotheses on its function in ID and hearing loss. However, its involvement in the occurrence of metopic synostosis is still to be discussed as more investigation of patients with the 9p monosomy syndrome is required.
authors.affiliation: Unité de Génétique Médicale et Laboratoire Associé INSERM à l'Unité UMR_S 910, Faculté de Médecine, Université Saint-Joseph, rue de Damas B.P. 17-5208 Mar Mikhael, Beyrouth, 11042020 Lebanon ; Aix-Marseille Université, GMGF, Marseille, France ; INSERM, UMR_S 910, Marseille, France.
authors.forename: Nancy
authors.initials: N
authors.lastname: Choucair
authors.affiliation: Aix-Marseille Université, GMGF, Marseille, France ; INSERM, UMR_S 910, Marseille, France.
authors.forename: Cecile
authors.initials: C
authors.lastname: Mignon-Ravix
authors.affiliation: Aix-Marseille Université, GMGF, Marseille, France ; INSERM, UMR_S 910, Marseille, France ; Département de Génétique Médicale, Assitance Publique Hôpitaux de Marseille, Hôpital d'Enfants de La Timone, Marseille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cacciagli
authors.affiliation: Unité de Génétique Médicale et Laboratoire Associé INSERM à l'Unité UMR_S 910, Faculté de Médecine, Université Saint-Joseph, rue de Damas B.P. 17-5208 Mar Mikhael, Beyrouth, 11042020 Lebanon.
authors.forename: Joelle
authors.initials: J
authors.lastname: Abou Ghoch
authors.affiliation: Neuropediatrics Department, Lebanese University, Beirut, Lebanon.
authors.forename: Ali
authors.initials: A
authors.lastname: Fawaz
authors.affiliation: Unité de Génétique Médicale et Laboratoire Associé INSERM à l'Unité UMR_S 910, Faculté de Médecine, Université Saint-Joseph, rue de Damas B.P. 17-5208 Mar Mikhael, Beyrouth, 11042020 Lebanon ; Institut Jérôme Lejeune, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.affiliation: Aix-Marseille Université, GMGF, Marseille, France ; INSERM, UMR_S 910, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
authors.affiliation: Unité de Génétique Médicale et Laboratoire Associé INSERM à l'Unité UMR_S 910, Faculté de Médecine, Université Saint-Joseph, rue de Damas B.P. 17-5208 Mar Mikhael, Beyrouth, 11042020 Lebanon.
authors.forename: Eliane
authors.initials: E
authors.lastname: Chouery
keywords: Hearing loss; Intellectual disability; Monosomy 9p; Protein tyrosine phosphatase receptor delta; Trigonocephaly