Tricho-rhino-phalangeal syndrome type I as a “cis-ruption disorder” caused by a...

• Author(s): Marques, Bárbara ; Ferreira, Cristina ; Araújo, Carlos ; Vieira, Luis ; Martins, Márcia ; Pinto, Maximina ; Dias, Cristina ; David, Dezső
• Date: 2011
• Persistent ID: http://hdl.handle.net/10400.18/166
• Origin: Repositório Científico do Instituto Nacional de Saúde
• Subject(s): Balanced translocation; Tricho-rhinophalangeal syndrome type I; Position effect; cisruption disorder; Doenças Genéticas
• Document Type: Conference Object
• Language: English

Description

Tricho-rhino-phalangeal syndrome type I (TRPS I; OMIM 190350) and type II (OMIM 150230) are two forms of the rare autosomal-dominant TRP malformation syndrome localised in 8q23.3–24.1. TRPS I is generally caused by point mutations or deletions of the TRPS1 gene, whereas type II is characterised by the presence of multiple cartilage exostoses (EXT) and deletions comprising the TRPS1 and EXT1 genes. In the present study, we have mapped and sequenced the breakpoints of a balanced familial translocation [t(8;13)(q23.3;q21.32)] segregating with mild TRPS I and analysed the TRPS1 candidate gene. The proband, in addition to features compatible with TRPS I, also presented developmental delay and severe mental retardation. The pathogenic chromosome 8 breakpoint was localised within a transposon type I element at 116.768 Mb, 87 kb from the TRPS1 5′ end. The breakpoint on chromosome 13 was localised within a gene-poor region at 65.101 Mb, and the nearest gene, 1.5 Mb distal from the breakpoint, is protocadherin 9 (PCDH9). Analysis of the three affected relatives by the 33K tiling BAC array and of the proband by 2.7-M high-resolution oligonucleotide array painting did not reveal additional genomic variation. Furthermore, mutation screening of the TRPS1 also did not reveal any alteration. Finally, expression studies of TRPS1 performed from LCLs indicate that inter-individual variation is higher than the expected gene expression changes induced by the translocation. Although the reason underlying the severe mental retardation observed in the proband is unknown, the available data indicate that this is not associated with the translocation. As far as we know, this is the first reported case of position effect or “cis-ruption” causing TRPS I. Finally, further studies are necessary to unveil the molecular pathogenic mechanisms of this “cis-ruption disorder” triggered by chromosometranslocation.