Germline DNA copy number variation in familial and early-onset breast cancer

Introduction: Genetic factors predisposing individuals to cancer remain elusive in the majority of patients with a familial or clinical history suggestive of hereditary breast cancer. Germline DNA copy number variation (CNV) has recently been implicated in predisposition to cancers such as neuroblastomas as well as prostate and colorectal cancer. We evaluated the role of germline CNVs in breast cancer susceptibility, in particular those with low population frequencies (rare CNVs), which are more likely to cause disease." Methods: Using whole-genome comparative genomic hybridization on microarrays, we screened a cohort of women fulfilling criteria for hereditary breast cancer who did not carry BRCA1/BRCA2 mutations. Results: The median numbers of total and rare CNVs per genome were not different between controls and patients. A total of 26 rare germline CNVs were identified in 68 cancer patients, however, a proportion that was significantly different (P = 0.0311) from the control group (23 rare CNVs in 100 individuals). Several of the genes affected by CNV in patients and controls had already been implicated in cancer. Conclusions: This study is the first to explore the contribution of germline CNVs to BRCA1/2-negative familial and early-onset breast cancer. The data suggest that rare CNVs may contribute to cancer predisposition in this small cohort of patients, and this trend needs to be confirmed in larger population samples.Brazilian National Institute of Science and Technology in Oncogenomics [FAPESP 2008/57887-9, CNPq 573589/08-9, FAPESP (2009/00898-1)]Brazilian National Institute of Science and Technology in Oncogenomic

PARTIAL MONOSOMY and PARTIAL TRISOMY 18 in 2 OFFSPRING of CARRIER of PERICENTRIC INVERSION of CHROMOSOME 18

UNIV São Paulo,INST BIOCIENCIAS,DEPT BIOL,GENET HUMANA LAB,São Paulo,BRAZILAPAE,CTR HABILITACAO,São Paulo,BRAZILESCOLA PAULISTA MED,São Paulo,BRAZILESCOLA PAULISTA MED,São Paulo,BRAZILWeb of Scienc

The clinical impact of chromosomal rearrangements with breakpoints upstream of the SOX9 gene: two novel de novo balanced translocations associated with acampomelic campomelic dysplasia

Abstract Background The association of balanced rearrangements with breakpoints near SOX9 [SRY (sex determining region Y)-box 9] with skeletal abnormalities has been ascribed to the presumptive altering of SOX9 expression by the direct disruption of regulatory elements, their separation from SOX9 or the effect of juxtaposed sequences. Case presentation We report on two sporadic apparently balanced translocations, t(7;17)(p13;q24) and t(17;20)(q24.3;q11.2), whose carriers have skeletal abnormalities that led to the diagnosis of acampomelic campomelic dysplasia (ACD; MIM 114290). No pathogenic chromosomal imbalances were detected by a-CGH. The chromosome 17 breakpoints were mapped, respectively, 917–855 kb and 601–585 kb upstream of the SOX9 gene. A distal cluster of balanced rearrangements breakpoints on chromosome 17 associated with SOX9-related skeletal disorders has been mapped to a segment 932–789 kb upstream of SOX9. In this cluster, the breakpoint of the herein described t(17;20) is the most telomeric to SOX9, thus allowing the redefining of the telomeric boundary of the distal breakpoint cluster region related to skeletal disorders to 601–585 kb upstream of SOX9. Although both patients have skeletal abnormalities, the t(7;17) carrier presents with relatively mild clinical features, whereas the t(17;20) was detected in a boy with severe broncheomalacia, depending on mechanical ventilation. Balanced and unbalanced rearrangements associated with disorders of sex determination led to the mapping of a regulatory region of SOX9 function on testicular differentiation to a 517–595 kb interval upstream of SOX9, in addition to TESCO (Testis-specific enhancer of SOX9 core). As the carrier of t(17;20) has an XY sex-chromosome constitution and normal male development for his age, the segment of chromosome 17 distal to the translocation breakpoint should contain the regulatory elements for normal testis development. Conclusions These two novel translocations illustrate the clinical variability in carriers of balanced translocations with breakpoints near SOX9. The translocation t(17;20) breakpoint provides further evidence for an additional testis-specific SOX9 enhancer 517 to 595 kb upstream of the SOX9 gene

Estudo de soluções de difusão e radiação para a climatização de uma carruagem de comboio

Trabalho final de mestrado para obtenção do grau de Mestre em Engenharia MecânicaA climatização tem ganho maior importância nos novos projetos de carruagens de materiais circulantes visto que uma das principais queixas dos passageiros é a má climatização das mesmas. No entanto a falta de informação sobre este tema ainda é muito elevada tornando este trabalho mais desafiante. A climatização dos transportes ferroviários é feita com recurso a sistemas de climatização de expansão direta utilizando um fluido refrigerante como permutador de calor entre o meio a climatizar e o espaço exterior. Após a produção de calor, ou frio, é necessário definir-se qual o meio de transmitir esse calor para o meio ambiente, para isso é utilizado vários tipos de difusores, variando a velocidade de insuflação e o jato de ar insuflado. Com isso é necessária uma seleção minuciosa de modo a obter o melhor conforto térmico. O presente projeto teve como foco estudar e entender qual o melhor sistema de difusão de ar para a climatização de uma carruagem. Para obter-se uma conclusão foi necessário o estudo e determinação das cargas térmicas para, deste modo, calcular-se os caudais de insuflação necessários. Para a realização do cálculo das cargas foi utilizado o programa DesignBuilder. Outro objetivo foi o estudo do aquecimento por um sistema misto, entre aquecimento por radiação e por difusão de ar. Para determinar-se a melhor solução de difusão de ar realizou-se vários estudos CFD (Computação em Dinâmica dos Fluidos), com recurso ao mesmo programa utilizado para o cálculo das cargas térmicas tendo sido possível observar que o melhor resultado obteve-se quando a difusão de ar foi feita por meio de três difusores de teto. Dois deles, situados por cima da fila de passageiros adjacente ao corredor, com um fluxo unidirecional descendente e o outro difusor situado no centro do teto com fluxo de ar bidirecional. Concluiu-se, igualmente, que a utilização de aquecimento radiante, com a conjunção de um sistema de difusão de ar, melhora o conforto térmico diminuindo o grau de insatisfação dos passageiros.Air conditioning has gained a great importance in the new design projects for rail vehicles carriages, once one of the main complaints of passengers is poor air conditioning. However, the lack of information on this topic is still very high, making this work more challenging. The air conditioning made by rail transport is made using direct expansion air conditioning systems using a refrigerant fluid as a heat exchanger between the air conditioning medium and the outside space. After the production of heat, or cold, it is necessary to define which means of transmitting this heat to the environment, for this it is used several types of diffusers, varying the insufflation speed and the inflated air jet. Therefore, a thorough selection is necessary in order to obtain the best thermal comfort. The present project focused on studying and understanding the best air diffusion system for the air conditioning of a coach in Copenhagen, Denmark. To reach a conclusion, it was necessary to study and determine the heat loads in order to calculate the required insufflation rates. Another objective was the study of heating by a mixed system, between heating by radiation and by air diffusion. With this, it was possible to observe that the best result was obtained when the air diffusion was made through three ceiling diffusers. Two of them, located above the passenger row adjacent to the corridor, with a unidirectional downward flow and the other diffuser located in the center of the ceiling with bidirectional air flow. It was also concluded that the use of radiant heating, namely floor and side panels, improves thermal comfort by reducing the degree of passenger dissatisfaction.N/

Distribution of CGG Repeats and FRAXAC1/DXS548 Alleles in South American Populations

In order to assess the molecular variability related to fragile X (FMR1 locus), we investigated the distribution of CGG repeats and DXS548/FRAXAC1 haplotypes in normal South American populations of different ethnic backgrounds. Special attention was given to Amerindian Wai-Wai (Northern Brazil) and Ache (Paraguay), as well as to Brazilian isolated communities of African ancestry, the remnants of quilombos. Comparison of samples from quilombos, Amerindians, and the ethnically mixed, but mainly European-derived population of Sã o Paulo revealed that the 30-copy allele of the fragile X gene is the most frequent in all groups. A second peak at 20 repeats was present in the population of Sã o Paulo only, confirming this as a European peculiarity. The distribution of DXS548 and FRAXAC1 alleles led to a high expected heterozygosity in African Brazilians, followed by that observed in the population of Sã o Paulo. Amerindians showed the lowest diversity in CGG repeats and DXS548/FRAXAC1 haplotypes. Some rare alleles, for example, the 148-bp (FRAXAC1) or 200-bp (DXS548) variants, which seem to be almost absent in Europe, occurred in higher frequencies among African Brazilians. This suggests a general trend for higher genetic diversity among Africans; these rarer alleles could be African in origin and would have been lost or possibly were not present in the groups that gave rise to the Europeans

Mining Novel Candidate Imprinted Genes Using Genome-Wide Methylation Screening and Literature Review

Large-scale transcriptome and methylome data analyses obtained by high-throughput technologies have been enabling the identification of novel imprinted genes. We investigated genome-wide DNA methylation patterns in multiple human tissues, using a high-resolution microarray to uncover hemimethylated CpGs located in promoters overlapping CpG islands, aiming to identify novel candidate imprinted genes. Using our approach, we recovered ~30% of the known human imprinted genes, and a further 168 candidates were identified, 61 of which with at least three hemimethylated CpGs shared by more than two tissue types. Thirty-four of these candidate genes are members of the protocadherin cluster on 5q31.3; in mice, protocadherin genes have non-imprinted random monoallelic expression, which might also be the case in humans. Among the remaining 27 genes, ZNF331 was recently validated as an imprinted gene, and six of them have been reported as candidates, supporting our prediction. Five candidates (CCDC166, ARC, PLEC, TONSL, and VPS28) map to 8q24.3, and might constitute a novel imprinted cluster. Additionally, we performed a comprehensive compilation of known human and mice imprinted genes from literature and databases, and a comparison among high-throughput imprinting studies in humans. The screening for hemimethylated CpGs shared by multiple human tissues, together with the extensive review, appears to be a useful approach to reveal candidate imprinted genes

Recurrent Deletion of ZNF630 at Xp11.23 Is Not Associated With Mental Retardation

ZNF630 is a member of the primate-specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41, ZNF81, and ZNF674 have been shown to be involved in mental retardation. This suggests that mutations of ZNF630 might influence cognitive function. Here, we detected 12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe. The breakpoints were analyzed in 10 families, and in all cases they were located within two segmental duplications that share more than 99% sequence identity, indicating that the deletions resulted from non-allelic homologous recombination. In 2,121 healthy male controls, 10 ZNF630 deletions were identified. In total, there was a 1.6-fold higher frequency of this deletion in males with mental retardation as compared to controls, but this increase was not statistically significant (P-value = 0.174). Conversely, a 1.9-fold lower frequency of ZNF630 duplications was observed in patients, which was not significant either (P-value = 0.163). These data do not show that ZNF630 deletions or duplications are associated with mental retardation. (C) 2010 Wiley-Liss, Inc.status: publishe

Recurrent Deletion of ZNF630 at Xp11.23 Is Not Associated With Mental Retardation How to Cite this Article

ZNF630 is a member of the primate-specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41, ZNF81, and ZNF674 have been shown to be involved in mental retardation. This suggests that mutations of ZNF630 How to Cite this Article: 638 might influence cognitive function. Here, we detected 12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe. The breakpoints were analyzed in 10 families, and in all cases they were located within two segmental duplications that share more than 99% sequence identity, indicating that the deletions resulted from non-allelic homologous recombination. In 2,121 healthy male controls, 10 ZNF630 deletions were identified. In total, there was a 1.6-fold higher frequency of this deletion in males with mental retardation as compared to controls, but this increase was not statistically significant (P-value ¼ 0.174). Conversely, a 1.9-fold lower frequency of ZNF630 duplications was observed in patients, which was not significant either (P-value ¼ 0.163). These data do not show that ZNF630 deletions or duplications are associated with mental retardation.

Regulatory variants of FOXG1 in the context of its topological domain organisation

FOXG1 syndrome is caused by FOXG1 intragenic point mutations, or by long-range position effects (LRPE) of intergenic structural variants. However, the size of the FOXG1 regulatory landscape is uncertain, because the associated topologically associating domain (TAD) in fibroblasts is split into two domains in embryonic stem cells (hESC). Indeed, it has been suggested that the pathogenetic mechanism of deletions that remove the stem-cell-specific TAD boundary may be enhancer adoption due to ectopic activity of enhancer(s) located in the distal hESC-TAD. Herein we map three de novo translocation breakpoints to the proximal regulatory domain of FOXG1. The classical FOXG1 syndrome in these and in other translocation patients, and in a patient with an intergenic deletion that removes the hESC-specific TAD boundary, do not support the hypothesised enhancer adoption as a main contributor to the FOXG1 syndrome. Also, virtual 4 C and HiC-interaction data suggest that the hESC-specific TAD boundary may not be critical for FOXG1 regulation in a majority of human cells and tissues, including brain tissues and a neuronal progenitor cell line. Our data support the importance of a critical regulatory region (SRO) proximal to the hESC-specific TAD boundary. We further narrow this critical region by a deletion distal to the hESC-specific boundary, associated with a milder clinical phenotype. The distance from FOXG1 to the SRO ( > 500 kb) highlight a limitation of ENCODE DNase hypersensitivity data for functional prediction of LRPE. Moreover, the SRO has little overlap with a cluster of frequently associating regions (FIREs) located in the proximal hESC-TAD