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.

Keywords: Hearing loss; Intellectual disability; Monosomy 9p; Protein tyrosine phosphatase receptor delta; Trigonocephaly.

Fig. 1

Clinical and genetic findings in the proband. a Representation of deleted regions within PTPRD. Black bars represent the deleted segments whereas the green one represents the BAC clone CTD-L2154L8 used in FISH. b Photograph of the proband at 3 years 6 months. The patient shows trigonocephaly, scaphocephaly, midface hypoplasia, a flat nose, a depressed nasal bridge, downslanting palpebral fissures, low set and large ears, a long philtrum, and a drooping mouth c FISH analysis confirming the presence of intron 8 on chromosome 9p. Arrowheads in red indicate a centromeric probe on chr9, and arrows in green indicate CTD-2154L8 mapping IVS8

Fig. 2

Dosage of PTPRD gene content using quantitative PCR. The bars represent the relative quantification of each sample. a The proband has zero copies of the first deletion within the PTPRD gene (chr9:8,527,597-9,248,069) and b zero copies of the second deletion touching this gene (chr9:9,316,105-9,491,477) whereas his parents and brother have a single copy compared to controls. P: patient, F: father, M: mother, B: brother, C1,C2, and C3: controls

Fig. 3

Expression of PTPRD in different tissues. Expression of PTPRD (top panels) and GAPGH (bottom panels) in a 13 human tissues and b 12 regions of the human brain. Several transcripts were found in the brain and in the heart, in addition to a high expression in the brain, testis, lung, retina, and colon. Conversely, PTPRD transcripts were found at low levels in the liver, kidney, and fibroblasts, and absent in lymphocytes

Fig. 4

RT-PCR amplifications along the PTPRD gene and expression of IL1RAPL1 in fibroblasts using Q-PCR. a RT-PCR amplifications indicate that no PTPRD transcript is found in the patient (P) in comparison to the control (C). GAPDH is used as an amplification control b Absence of the PTPRD transcript in the patient and a reduction of 92 % in the expression of IL1RAPL1 in fibroblasts

Fig. 5

Graphical mapping of molecularly 9p24 interstitial deletions diagnosed in previously reported patients with trigonocephaly (blue bars) and in the patient here described (red bar)