Browsing by Author "Dias, Cristina"
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- Co-segregation of trichorhinophalangeal syndrome with a t(8;13)(q23.3;q21.31) familial translocation that appears to increase TRPS1 gene expressionPublication . David, Dezső; Marques, Bárbara; Ferreira, Cristina; Araújo, Carlos; Vieira, Luís; Soares, Gabriela; Dias, Cristina; Pinto, MaximinaTrichorhinophalangeal syndrome type I (TRPS I) is a rare autosomal dominant syndrome caused by haploinsufficiency of TRPS1 due to point mutations or deletions. Here we report the first familial TRPS I due to a t(8;13)(q23.3;q21.31) translocation breakpoint <100 kb from the 5’ end of TRPS1. Based on the additional abnormalities observed exclusively in the index patient that are mainly compatible with clinical features of TRPS, her phenotype was defined as expanded TRPS I including brain malformations and intellectual disability. Initial analyses did not reveal any genetic defect affecting TRPS1 or any genomic alteration within the breakpoint regions or elsewhere in the genome. The pathogenic chromosome 8q23.3 breakpoint is at position g.116,768,309_116,768,310 within a transposon type I element, 87 kb from the TRPS1 5’ end. The 13q21.31 breakpoint is within a tandem repeat region at position g.65,101,509_65,101,510 (genome assembly GRCh37/hg19). This breakpoint is flanked by protocadherin 9 (PCDH9) and protocadherin 20 (PCDH20). As an outcome of the translocation, an evolutionarily conserved non-coding VISTA enhancer element from 13q21.31 is placed within the TRPS1 5’ region, 1,294 bp from the breakpoint. The increased expression of TRPS1 found by three independent methods is most probably translocation allele derived and driven by the translocated enhancer element. The index patient’s expanded phenotype presumably involves the epithelial-to-mesenchymal transition pathway that may be due to TRPS1 overexpression. Together, these findings support that the reported translocation associated phenotypes are “cis-ruption” and TRPS1 overexpression related, the latter most probably caused by the novel enhancer element in the TRPS1 5’ region.
- Development of NIPBL locus-specific database using LOVD: from novel mutations to further genotype-phenotype correlations in Cornelia de Lange SyndromePublication . Oliveira, Jorge; Dias, Cristina; Redeker, Egbert; Costa, Eurico; Silva, João; Lima, Margarida Reis; Den Dunnen, Johan T.; Santos, RosárioThe establishment of Locus Specific Databases (LSDB) is a crucial aspect for the Human Genetics field and one of the aims of the Human Variation Project. We report the development of a publicly accessible LSDB for the NIPBL gene (http://www.lovd.nl/NIPBL) implicated in Cornelia de Lange Syndrome (CdLS). This rare disorder is characterized by developmental and growth retardation, typical facial features, limb anomalies, and multiple organ involvement. Mutations in the NIPBL gene, the product of which is involved in control of the cohesion complex, account for over half of the patients currently characterized. The NIPBL LSDB adopted the Leiden Open Variation database (LOVD) software platform, which enables the comprehensive Web-based listing and curation of sequence variations and associated phenotypical information. The NIPBL-LOVD database contains 199 unique mutations reported in 246 patients (last accessed April 2010). Information on phenotypic characteristics included in the database enabled further genotype–phenotype correlations, the most evident being the severe form of CdLS associated with premature termination codons in the NIPBL gene. In addition to the NIPBL LSDB, 50 novel mutations are described in detail, resulting from a collaborative multicenter study. Hum Mutat 31:1216–1222, 2010. © 2010 Wiley-Liss, Inc.
- Interstitial dup(6)(q22.3q24) characterized by cCGH resulting from familial inv ins(6)(p11.2q25.3q22.3): case reportPublication . Oliva Teles, Natália; Mota Ribeiro, Manuela; Marques, Bárbara; Correia, Hildeberto; Aires-Pereira, Joana; Dias, Cristina; Furtuna, Ana
- Private dysferlin exon skipping mutation (c.5492G>A) with a founder effect reveals further alternative splicing involving exons 49-51Publication . Santos, Rosário; Oliveira, Jorge; Vieira, Emília; Coelho, Teresa; Carneiro, António Leite; Evangelista, Teresinha; Dias, Cristina; Fortuna, Ana; Geraldo, Argemiro; Negrão, Luís; Guimarães, António; Bronze-da-Rocha, ElsaThe allelic muscle disorders known as limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy and distal anterior compartment myopathy result from defects in dysferlin—a sarcolemma-associated protein involved in membrane repair. Mutation screening in the dysferlin gene (DYSF) enabled the identification of seven Portuguese patients presenting the variant c.5492G4A, which was observed to promote skipping of exon 49 (p.Gly1802ValfsX17). Several residually expressed products of alternative splicing also involving exons 50 and 51 were detected in the leukocytes and muscle of both patients and normal controls. Quantitative transcript analysis confirmed these results and revealed that D49/D50 transcripts were predominant in blood. Although the patients were apparently unrelated, the c.5492G4A mutation was found in linkage disequilibrium with a particularly rare haplotype in the population, corroborating the hypothesis of a common origin. Despite the presence of the same mutation on the same haplotype background, onset of the disease was heterogeneous, with either proximal or distal muscle involvement.
- Tricho-rhino-phalangeal syndrome type I as a “cis-ruption disorder” caused by a translocationPublication . Marques, Bárbara; Ferreira, Cristina; Araújo, Carlos; Vieira, Luís; Martins, Márcia; Pinto, Maximina; Dias, Cristina; David, DezsőTricho-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.