The molecular pathogenesis of chromosome translocation-associated “cis-ruption” disorders

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Partial trisomy of the pericentromeric region of chromosome 5 in a girl with Binder phenotype

Publication . Hadzsiev, Kinga; Dávid, Dezső; Szabó, Gyula; Czakó, Márta; Melegh, Béla; Kosztolányi, György

The patient reported here displayed the most characteristic features of Binder syndrome (OMIM: 155050), a rare maxillonasal malformation with unknown etiology. She was sent for genetic evaluation at the age of 10 years because of facial dysmorphism and borderline intellectual disability. Cytogenetic analyses showed a de novo supernumerary small ring chromosome with a pericentromeric region of chromosome 5 in all lymphocytes. Array analysis revealed that the marker contains a 20,950 kb genomic region comprising cytogenetic bands 5p14.1 to q11.1. Altogether 7 reports have been published in the literature with partial trisomy of chromosome 5 overlapping with our case. These 8 cases were analysed for phenotype/genotype correlation which suggested that the maxillonasal anomalies of Binder phenotype and trisomy of pericentromeric region of chromosome 5 may be in causal relationship. Further functional annotation studies of genes localized in this genomic region should take this into consideration. To the best of our knowledge, this is the first report on a patient with association of a chromosome abnormality and clinical characteristics of Binder phenotype.

2014-12-20Journal article

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Identification and genotype-phenotype correlation of structural chromosomal alterations

Publication . David, Dezso

2016-02Conference object

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Identification of OAF and PVRL1 as candidate genes for an ocular anomaly characterized by Peters anomaly type 2 and ectopia lentis

Publication . David, Dezso; Anand, D.; Araújo, C.; Gloss, B.; Fino, J.; Dinger, M.; Lindahl, P.; Pöyhönen, M.; Hannele, L.; Lavinha, J.

Keratolenticular dysgenesis (KLD) and ectopia lentis are congenital eye defects. The aim of this study is the identification of molecular genetic alterations responsible for those ocular anomalies with neurologic impairment in an individual with a de novo balanced chromosome translocation t(11;18)(q23.3;q11.2)dn. Disruption of OAF, the human orthologue of the Drosophila oaf, by the 11q23.3 breakpoint results in reduced expression of this transcriptional regulator. Furthermore, four most likely nonfunctional chimeric transcripts comprising up to OAF exon 3, derived from the der(11) allele, have also been identified. This locus has been implicated by publicly available genome-wide association data in corneal disease and corneal topography. The expression of the poliovírus receptor-related 1(PVRL1) or nectin cell adhesion molecule 1 (NECTIN1), a paralogue of nectin cell adhesion molecule 3 (PVRL3) associated with congenital ocular defects, situated 500 kb upstream from 11q23.3 breakpoint, is increased. The 18q11.2 breakpoint is localized between cutaneous T-cell lymphoma-associated antigen 1(CTAGE1) and retinoblastoma binding protein 8 (RBBP8) genes. Genomic imbalance that could contribute to the observed phenotype was excluded. Analysis of gene expression datasets throughout normal murine ocular lens embryogenesis suggests that OAF expression is significantly enriched in the lens from early stages of development through adulthood, whereas PVRL1 is lens-enriched until E12.5 and then down-regulated. This contrasts with the observation that the proposita's lymphoblastoid cell lines exhibit low OAF and high PVRL1 expression as compared to control, which offers further support that the alterations described above are most likely responsible for the clinical phenotype. Finally, gene interaction topology data for PVRL1 also agree with our proposal that disruption of OAF by the translocation breakpoint and misregulation of PVRL1 due to a position effect contribute to the observed ocular and neurological phenotype.

2018-03Journal article

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