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Fernando de Noronha (Distrito Estadual), Brazil

Polla D.L.,Catholic University of Brasilia | Polla D.L.,Radboud University Nijmegen | Cardoso M.T.O.,Nucleo de Genetica da Secretaria de Saude Do Distrito Federal | Cardoso M.T.O.,Catholic University of Brasilia | And 9 more authors.
PLoS ONE | Year: 2015

Genetic disorders of the skeleton comprise a large group of more than 450 clinically distinct and genetically heterogeneous diseases associated with mutations in more than 300 genes. Achieving a definitive diagnosis is complicated due to the genetic heterogeneity of these disorders, their individual rarity and their diverse radiographic presentations. We used targeted exome sequencing and designed a 1.4Mb panel for simultaneous testing of more than 4,800 exons in 309 genes involved in skeletal disorders. DNA from 69 individuals from 66 families with a known or suspected clinical diagnosis of a skeletal disorder was analyzed. Of 36 cases with a specific clinical hypothesis with a known genetic basis, mutations were identified for eight cases (22%). Of 20 cases with a suspected skeletal disorder but without a specific diagnosis, four causative mutations were identified. Also included were 11 cases with a specific skeletal disorder but for which there was at the time no known associated gene. For these cases, one mutation was identified in a known skeletal disease genes, and re-evaluation of the clinical phenotype in this case changed the diagnoses from osteodysplasia syndrome to Apert syndrome. These results suggest that the NGS panel provides a fast, accurate and cost-effective molecular diagnostic tool for identifying mutations in a highly genetically heterogeneous set of disorders such as genetic skeletal disorders. The data also stress the importance of a thorough clinical evaluation before DNA sequencing. The strategy should be applicable to other groups of disorders in which the molecular basis is largely known. Copyright: © 2015 Polla et al. Source

Marques F.,Catholic University of Brasilia | Heredia R.,Nucleo de Genetica da Secretaria de Saude Do Distrito Federal | de Oliveira C.,Nucleo de Genetica da Secretaria de Saude Do Distrito Federal | de Oliveira C.,University of Brasilia | And 4 more authors.
American Journal of Medical Genetics, Part A | Year: 2015

Craniosynostosis is defined as a premature fusion of at least one cranial suture, which can be accompanied by other findings. Of syndromic cases, 14-22% have been associated with chromosomal rearrangements. This report describes a Brazilian boy with syndromic craniosynostosis who also presented with intellectual disability, microcephaly, frontal bossing, bitemporal narrowing, short neck, syndactyly, and cardiac defects. Chromosome banding showed an apparently normal male karyotype. Subsequent chromosomal microarray analysis (CMA) using the Affymetrix CytoScan 750 K Array showed a duplication of 2.1 Mb on chromosome 17q and a deletion of 1.4 Mb on chromosome 20q. The data suggested an unbalanced translocation, which was confirmed by fluorescence in-situ hybridization analysis (FISH). While there are several reports in the literature of chromosome 17q duplication syndrome accompanied by partial monosomies of other chromosomes, this is the first case featuring partial monosomy of 20q. The patients phenotype is generally consistent with 17q duplication syndrome, however craniosynostosis has rarely been associated with this chromosomal anomaly. © 2014 Wiley Periodicals, Inc. Source

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