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‣ Reliability of short comparative genomic hybridization in fibroblasts and blastomeres for a comprehensive aneuploidy screening: first clinical application

RIUS, M.; OBRADORS, A.; DAINA, G.; CUZZI, J.; MARQUES, L.; CALDERON, G.; VELILLA, E.; MARTINEZ-PASSARELL, O.; OLIVER-BONET, M.; BENET, J.; NAVARRO, J.
Fonte: OXFORD UNIV PRESS Publicador: OXFORD UNIV PRESS
Tipo: Artigo de Revista Científica
Português
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BACKGROUND: Comparative genomic hybridization (CGH) is a valuable alternative to fluorescence in situ hybridization (FISH) for preimplantation genetic screening (PGS) because it allows full karyotype analysis. However, this approach requires the cryopreservation of biopsied embryos until results are available. The aim of this study is to reduce the hybridization period of CGH, in order to make this short-CGH technique suitable for PGS of Day-3 embryos, avoiding the cryopreservation step. METHODS: Thirty-two fibroblasts from six aneuploid cell lines (Coriell) and 48 blastomeres from 10 Day-4 embryos, discarded after PGS by FISH with 9 probes (9-chr-FISH), were analysed by short-CGH. A reanalysis by the standard 72 h-CGH and FISH using telomeric probes was performed when no concordant results between short-CGH and FISH diagnosis were observed. The short-CGH was subsequently applied in a clinical case of advanced maternal age. RESULTS: In 100% of the fibroblasts analysed, the characteristic aneuploidies of each cell line were detected by short-CGH. The results of the 48 blastomeres screened by short-CGH were supported by both 72 h-CGH results and FISH reanalysis. The chromosomes most frequently involved in aneuploidy were 22 and 16, but aneuploidies for the other chromosomes...

‣ Identificação de mutações e rastreamento gênico familiar em famílias brasileiras com neoplasia endócrina múltipla tipo 1; Identification of germline mutations and familial genetic screening in brazilian families with multiple endocrine neoplasia type 1

Toledo, Rodrigo de Almeida
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 24/04/2007 Português
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A Neoplasia Endócrina Múltipla tipo 1 (NEM1, OMIM 131100) é uma doença essencialmente caracterizada por sua complexidade clínica. A NEM1 afeta tanto tecidos endócrinos quanto tecidos não-endócrinos; apresenta tanto tumores malignos quanto tumores benignos; e apresenta extensa variabilidade clínica inter e intra-familiar quanto aos tipos de tumores e quanto à ordem de desenvolvimento e detecção clínica desses tumores. Em sua forma familiar, a NEM1 é transmitida por um padrão de herança autossômico dominante com elevada penetrância e é identificada pela presença de um parente de primeiro grau apresentando ao menos um tumor NEM1-relacionado. A realização do diagnóstico de NEM1 pode ser: a) clínico, pelo reconhecimento em único paciente de tumores em pelo menos duas das três glândulas endócrinas-alvo principais (paratireóides, hipófise e pâncreas endócrino) e/ou b) genético, pela identificação de mutação germinativa no gene responsável pela doença (MEN1). A grande maioria dos casos NEM1 (90%) apresentam mutações inativadoras no gene MEN1. Não há correlações descritas até o momento entre o genótipo e o fenótipo. Não há também regiões preferenciais (hot-spots) para as mutações no gene MEN1. Além disto...

‣ The impact of clinical and genetic screenings on the management of the multiple endocrine neoplasia type 1

Lourenço-Jr,Delmar Muniz; Toledo,Rodrigo Almeida; Coutinho,Flavia Lima; Margarido,Leontina Conceição; Siqueira,Sheila Aparecida Coelho; Santos,Marcelo Augusto Cortina Gonçalves dos; Montenegro,Fabio Luiz de Menezes; Machado,Marcel Cerqueira Cesar; Tol
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2007 Português
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PURPOSE: To perform clinical and genetic screening for multiple endocrine neoplasia type 1 (MEN1) in patients at the Academic Hospital of the University of São Paulo School of Medicine, and to analyze its impact on clinical management of patients with MEN1. METHODS: The clinical diagnosis of MEN1 was made in accordance with the Consensus on multiple endocrine neoplasias. Mutation analysis of the entire MEN1 tumor suppressor gene and genetic screening of at-risk family members were performed by direct sequencing. To analyze the implementation of genetic diagnosis, the studied patients were separated into 3 groups: MEN1 index cases (group I), clinically diagnosed MEN1 cases (group II), and genetically diagnosed MEN1 cases (group III). RESULTS: In total, 154 individuals were clinically and genetically studied. We identified 12 different MEN1 mutations. Fifty-two MEN1 cases were identified: 13 in group I, 28 in group II, and 11 in group III. The mean age in group III (27.0 years) was significantly lower than in groups I (39.5 years) and II (42.4 years; P = 0.03 and P = 0.01, respectively). Patients in groups I and II mostly presented 2 or 3 MEN1-related tumors, while 81.8% of those in group III presented 1 or no MEN1-related tumor. Additionally...

‣ Surgical decision-making affected by clinical and genetic screening of a novel kindred with von Hippel-Lindau disease and pancreatic islet cell tumors.

Curley, S A; Lott, S T; Luca, J W; Frazier, M L; Killary, A M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1998 Português
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OBJECTIVE: We report a unique, previously undescribed multigeneration kindred with von Hippel-Lindau (VHL) disease in whom clinical or genetic screening led to the detection of surgically resectable neoplastic disease in several family members. SUMMARY BACKGROUND DATA: Patients with VHL disease have a propensity to develop neoplasms of several different organ sites. Retinal angiomas, cerebellar and spinal hemangioblastomas, solid organ cysts, and renal carcinoma are common lesions; pheochromocytomas and pancreatic islet cell tumors occur less frequently but are important causes of morbidity and mortality. METHODS: A detailed pedigree was constructed based on clinical screening and family history that describes the development of pancreatic islet cell tumors in four of five female siblings. VHL mutation analysis was performed in an attempt to determine if genotype-phenotype correlations could be made in this interesting family. RESULTS: The age of onset of VHL-associated neoplasms for three affected siblings was in the third decade of life and in the fourth decade for the fourth sibling. The mother of the four siblings affected with pancreatic tumors developed bilateral pheochromocytomas in the seventh decade of life; she has no pancreatic or kidney tumors. We identified maternal transmission of a missense mutation in codon 238 in exon 3 of the VHL gene in the four affected siblings with pancreatic islet cell tumors. Mutation screening on unaffected family members showed no abnormalities in the VHL gene. Interestingly...

‣ Estimating the Efficacy and Efficiency of Cascade Genetic Screening

Krawczak, Michael; Cooper, David N.; Schmidtke, Jörg
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
Português
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Screening for genetic variants that predispose individuals or their offspring to disease may be performed at the general population level or may instead be targeted at the relatives of previously identified carriers. The latter strategy has come to be known as “cascade genetic screening.” Since the carrier risk of close relatives of known carriers is generally higher than the population risk, cascade screening is more efficient than population screening, in the sense that fewer individuals have to be genotyped per detected carrier. The efficacy of cascade screening, as measured by the overall proportion of carriers detected in a given population, is, however, lower than that of population-wide screening, and the respective inclusion rates vary according to the population frequency and mode of inheritance of the predisposing variants. For dominant mutations, we have developed equations that allow the inclusion rates of cascade screening to be calculated in an iterative fashion, depending upon screening depth and penetrance. For recessive mutations, we derived only equations for the screening of siblings and the children of patients. Owing to their mathematical complexity, it was necessary to study more extended screening strategies by simulation. Cascade screening turned out to result in low inclusion rates (<1%) when aimed at the identification of heterozygous carriers of rare recessive variants. Considerably higher rates are achievable...

‣ A transgenic approach for RNA interference-based genetic screening in mice

Peng, Shaohua; York, J. Philippe; Zhang, Pumin
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
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Genetic screening is the most powerful method through which to uncover gene function. It has been applied very successfully in lower organisms but seldom attempted in mammalian species because of their long generation time. In this study, we exploit RNA interference (RNAi) for its potential use in genetic screening in mice. We show that RNAi-induced gene knockdown can be generated through introducing small hairpin RNA-expressing constructs into the mouse as transgenes via conventional pronuclear injection. The knockdown effect can be transmitted for many generations in these transgenic animals. In a small-scale screening for developmental defects in the kidney, we uncovered a potential role of Id4 in the formation of the renal medulla. Our results demonstrate the feasibility of using RNAi for genetic screening in mice.

‣ An economic evaluation of a genetic screening program for Tay-Sachs disease.

Nelson, W B; Swint, J M; Caskey, C T
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /03/1978 Português
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The resolution of policy questions relating to medical genetic screening programs will not be without considerable difficulty. Examples include such issues as the optimal degree of screening program expansion, the relative values of screening for different genetic diseases, the appropriate sources of program funding (public vs. private), and the relative value of funding expanded genetic screening programs vs. research directed toward elimination of genetic traits themselves. Information on the net impact of the relevant alternatives is greatly needed, and this need will increase if the National Genetics Act receives funding approval. We have provided what is hopefully a contribution toward this end. While our analysis pertains to a specific disease and a specific screening program for that disease, the methodology is readily generalizable to other genetic diseases, as well as programs of any size or structure. Hopefully, this will serve to stimulate further research efforts that we believe are needed for the objective consideration of resource allocation alternatives.

‣ Newborn Genetic Screening for Hearing Impairment: A Preliminary Study at a Tertiary Center

Wu, Chen-Chi; Hung, Chia-Cheng; Lin, Shin-Yu; Hsieh, Wu-Shiun; Tsao, Po-Nien; Lee, Chien-Nan; Su, Yi-Ning; Hsu, Chuan-Jen
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 19/07/2011 Português
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Universal newborn hearing screening (UNHS) is of paramount importance for early identification and management of hearing impairment in children. However, infants with slight/mild, progressive, or late-onset hearing impairment might be missed in conventional UNHS. To investigate whether genetic screening for common deafness-associated mutations could assist in identifying these infants, 1017 consecutive newborns in a tertiary hospital were subjected to both newborn hearing screening using a two-step distortion-product otoacoustic emissions (DPOAE) screening and newborn genetic screening (NGS) for deafness. The NGS targeted 4 deafness-associated mutations commonly found in the Taiwanese population, including p.V37I (c.109G>A) and c.235delC of the GJB2 gene, c.919-2A>G of the SLC26A4 gene, and mitochondrial m.1555A>G of the 12S rRNA gene. The results of the NGS were then correlated to the results of the NHS. Of the 1017 newborns, 16 (1.6%) had unilateral DPOAE screening failure, and 22 (2.2%) had bilateral DPOAE screening failure. A total of 199 (19.6%) babies were found to have at least 1 mutated allele on the NGS for deafness, 11 (1.1%) of whom were homozygous for GJB2 p.V37I, 6 (0.6%) compound heterozygous for GJB2 p.V37I and c.235delC...

‣ Genetic Screening

Burke, Wylie; Tarini, Beth; Press, Nancy A.; Evans, James P.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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Current approaches to genetic screening include newborn screening to identify infants who would benefit from early treatment, reproductive genetic screening to assist reproductive decision making, and family history assessment to identify individuals who would benefit from additional prevention measures. Although the traditional goal of screening is to identify early disease or risk in order to implement preventive therapy, genetic screening has always included an atypical element—information relevant to reproductive decisions. New technologies offer increasingly comprehensive identification of genetic conditions and susceptibilities. Tests based on these technologies are generating a different approach to screening that seeks to inform individuals about all of their genetic traits and susceptibilities for purposes that incorporate rapid diagnosis, family planning, and expediting of research, as well as the traditional screening goal of improving prevention. Use of these tests in population screening will increase the challenges already encountered in genetic screening programs, including false-positive and ambiguous test results, overdiagnosis, and incidental findings. Whether this approach is desirable requires further empiric research...

‣ Genetic screening for homozygous and heterozygous familial hypercholesterolemia

Izar, Maria C; Machado, Valéria A; Fonseca, Francisco A
Fonte: Dove Medical Press Publicador: Dove Medical Press
Tipo: Artigo de Revista Científica
Publicado em 08/12/2010 Português
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Familial hypercholesterolemia (FH) is a common inherited disorder that results in premature atherosclerosis. Diagnosis of FH is suspected on the basis of clinical criteria, but confirmation requires genetic testing. In the era of statins, early diagnosis and initiation of treatment can modify disease progression and outcomes. Therefore, cascade screening with a combination of lipid concentration measurements and DNA testing should be used to identify relatives of index cases with a clinical diagnosis of FH. Autosomal dominant FH is related to mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Genetic screening of the LDLR gene is challenging to achieve at a feasible cost, especially in people who do not have a founder effect. Nucleotide sequencing of all exons and flanking splicing regions in combination with multiplex ligation probe amplification to detect large insertions or deletions is considered the gold-standard approach to screen for LDLR mutations. Alternatively, the cDNA can be sequenced; however, this procedure is not suitable for use in large populations, because of the need of RNA extraction. Multiplex analysis can be appropriate for population with founder effects or a low number of different mutations. Finally...

‣ Modeling the Impact of Genetic Screening Technologies on Healthcare: Theoretical Model for Asthma in Children

GUTIERREZ DE MESA Emma; HIDALGO Ignacio; CHRISTIDIS PANAYOTIS; CISCAR MARTINEZ JUAN CARLOS; VEGAS Eva; IBARRETA RUIZ DOLORES
Fonte: ADIS INTERNATIONAL LTD Publicador: ADIS INTERNATIONAL LTD
Tipo: Articles in Journals Formato: Printed
Português
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Objective: This study focuses on the potential impact of genome-based technologies on health care. Asthma in children was chosen as a case study and gene screening as the technology assessed to explore the cost-effectiveness of applying early genetic screening to newborns and preventive treatment to the population at risk. Early intervention could prevent progression and facilitate clinical management of the disease. From the elite group of genetic markers that have been associated with asthma-related phenotypes, ADAM33 was the first published candidate gene detected by a positional cloning approach, marking the entry of asthma research into the genomic era. The model was therefore initially set for an ex-ante analysis of the cost-effectiveness of applying the preventive programme to all the population presenting the ADAM33 genetic marker, with the idea of expanding to further markers and their combinations later on. Methods: According to the US NIH, Heart Lung and Blood Institute, four categories of asthma are considered. A Markov model consisting of six mutually exclusive disease states (including healthy and dead states) with a simulation horizon of 100 years was constructed, being the cycle length 1 year. Two different scenarios were defined. In scenario 1 genetic screening and preventive treatment are applied to all the population having the genetic marker and during the risk window from 0 to 6 years. In scenario 2 early genetic screening is applied to all newborns but preventive treatment only to children who present both wheezing and the genetic marker. The CEA was performed from third party payer and patient perspective after year 6. Conclusions: The cost-effectiveness of early genetic screening and of applying the preventive strategy to all the population presenting the selected ADAM33 marker remains on the borderline of cost-effectiveness. Nevertheless early genetic screening plus preventive treatment of all children with both wheezing and presenting the susceptibility genetic marker seems to be cost-effective. The model is a valuable tool for the ex-ante assessment of the cost-effectiveness of preventive schemes based on genetic screening. The value of modelling prior to clinical trials lies in informing study design and in setting priorities for future research.; JRC.J.4-Agriculture and Life Sciences in the Economy

‣ 'Inside-out', back-to-front: a model for clinical population genetic screening.

Shickle, D; Harvey, I
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1993 Português
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Developments in DNA technology have resulted in a dramatic increase in the number of genes identified. With the localisation of a gene it is possible to devise procedures suitable for mass carrier screening programmes. Until recently mass carrier screening was only possible for a limited number of disorders, for example, Tay-Sachs disease and haemoglobinopathies. Counselling possible carriers was based on estimations of risk. The momentum towards mass carrier screening is likely to be increased by gene therapy. Carrier screening for cystic fibrosis alone will have dramatic implications for genetic service provision as 4 to 5% of the UK population carry the CF gene. The potential for genetic screening of multifactorial diseases, for example, cancers, should also be considered. The existing organisation of genetic services is likely to be inadequate. A new specialty of clinical population genetics is required. A model is proposed of clinical population genetic screening programmes, organised under a 'common umbrella' led by a public health physician, while screening and follow up will remain the responsibility of the appropriate clinician.

‣ What next for preimplantation genetic screening? High mitotic chromosome instability rate provides the biological basis for the low success rate

Vanneste, Evelyne; Voet, Thierry; Melotte, Cindy; Debrock, Sophie; Sermon, Karen; Staessen, Catherine; Liebaers, Inge; Fryns, Jean-Pierre; D'Hooghe, Thomas; Vermeesch, Joris R.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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Preimplantation genetic screening is being scrutinized, as recent randomized clinical trials failed to observe the expected significant increase in live birth rates following fluorescence in situ hybridization (FISH)-based screening. Although these randomized clinical trials are criticized on their design, skills or premature stop, it is generally believed that well-designed and well-executed randomized clinical trials would resolve the debate about the potential benefit of preimplantation genetic screening. Since FISH can analyze only a limited number of chromosomal loci, some of the embryos transferred might be diagnosed as ‘normal’ but in fact be aneuploid for one or more chromosomes not tested. Hence, genome-wide array comparative genome hybridization screening enabling aneuploidy detection of all chromosomes was thought to be a first step toward a better design. We recently showed array screening indeed enables accurate determination of the copy number state of all chromosomes in a single cell. Surprisingly, however, this genome-wide array screening revealed a much higher frequency and complexity of chromosomal aberrations in early embryos than anticipated, with imbalances in a staggering 90% of all embryos. The mitotic error rate in cleavage stage embryos was proven to be higher than the meiotic aneuploidy rate and as a consequence...

‣ Stigmatization of carrier status: social implications of heterozygote genetic screening programs.

Kenen, R H; Schmidt, R M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1978 Português
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Possible latent psychological and social consequences ensuing from genetic screening programs need to be investigated during the planning phase of national genetic screening programs. The relatively few studies which have been performed to determine psychological, social, and economic consequences resulting from a genetic screening program are reviewed. Stigmatization of carrier-status, having major psychosocial implications in heterozygote genetic screening programs, is discussed and related to Erving Goffman's work in the area of stigmatization. Questions are raised regarding the relationship between such variables as religiosity and sex of the individual and acceptance of the status of newly identified carrier of a mutant gene. Severity of the deleterious gene and visibility of the carrier status are two important factors to consider in an estimation of potential stigma. Specific implications are discussed for four genetic diseases: Tay-Sachs, Sickle-Cell Anemia, Huntington's disease and Hemophilia.

‣ Medical and ethical issues in genetic screening--an academic view.

Holtzman, N A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1996 Português
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This article is intended to acquaint those whose principal concerns are the health and safety of workers with genetic screening and some of the medical and ethical issues it raises. Population-based genetic screening increasingly is being considered for predicting future disease in the person being screened. A major problem in screening for alleles that contribute to the development of common, multifactorial disorders is low sensitivity and positive predictive value. In many instances, no demonstrably effective prophylaxis or treatment is available to help those with positive test results. This creates ethical problems of assuring that testing is in the person's best interest and raises in turn issues of autonomy, discrimination, and privacy. Instead of screening for genetic predispositions to harm from workplace exposures, other means of improving the health of workers may bring greater benefits to a higher proportion of workers. The current state of genetic tests for chronic beryllium disease are considered. None are suitable for screening.

‣ Anàlisi citogenètica i monogènica en cèl·lula única diagnòstic genètic preimplantacional de doble factor /

Daina Noves, Gemma
Fonte: [Barcelona] : Universitat Autònoma de Barcelona, Publicador: [Barcelona] : Universitat Autònoma de Barcelona,
Tipo: Tesis i dissertacions electròniques; info:eu-repo/semantics/doctoralThesis Formato: application/pdf
Publicado em //2013 Português
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El diagnòstic genètic preimplantacional (PGD) permet diagnosticar embrions obtinguts mitjançant tècniques de reproducció assistida. L'objectiu principal del PGD és diagnosticar els embrions de parelles portadores de malalties hereditàries greus, per tal d'aconseguir el naixement d'individus sans. S'ha postulat que les aneuploïdies són, en molts casos, responsables de la infertilitat o del fracàs de les metodologies de fecundació in vitro (FIV) per això, s'ha desenvolupat una variant del PGD, el PGS (Preimplantational Genetic Screening). Aquest té com a objectiu estudiar alteracions cromosòmiques, ja siguin numèriques o estructurals. Fins a l'actualitat la tècnica més emprada per al diagnòstic d'aquest tipus d'alteracions ha estat la FISH (Hibridació in situ Fluorescent). Rutinàriament amb aquesta metodologia s'estudien 9 cromosomes dels 24 totals del complement. Una altra metodologia per a l'estudi d'aneuploïdies és la CGH (Hibridació Genòmica Comparada), aquesta permet analitzar citogenèticament tot el complement cromosòmic de la cèl·lula d'estudi. L'anàlisi conjunta de malalties monogèniques familiars i d'aneuploïdies de tot el complement cromosòmic conformen el diagnòstic genètic preimplantacional de doble factor (DF-DGP). El primer objectiu d'aquesta tesi ha estat dur a terme un estudi bàsic que permetés aprofundir en el coneixement de les aneuploïdies pre-meiòtiques existents en l'oòcit utilitzant la tècnica de CGH. Estudiant 157 oòcits immadurs de dones de diferents edats i indicacions...

‣ Anàlisi completa d'aneuploïdies d'origen femení i de malalties monogèniques en embrions el diagnòstic genètic preimplantacional de doble factor (DF-PGD) /

Obradors Cherta, Albert
Fonte: Bellaterra : Universitat Autònoma de Barcelona, Publicador: Bellaterra : Universitat Autònoma de Barcelona,
Tipo: Tesis i dissertacions electròniques; info:eu-repo/semantics/doctoralThesis Formato: application/pdf
Publicado em //2009 Português
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Consultable des del TDX; Títol obtingut de la portada digitalitzada; El Diagnòstic Genètic Preimplantacional (o DGP) és un conjunt de metodologies, que s'apliquen en el transcurs d'un cicle de reproducció assistida, i que permeten la selecció d'embrions sans en parelles afectes de malalties genètiques hereditàries com la fibrosi quística o l'hemofília, entre moltes altres. A més, també s'utilitza per realitzar un cribatge d'alteracions cromosòmiques (o aneuploïdies) que puguin afectar l'embrió, ja que s'ha evidenciat que aquestes són molt abundants en avortaments. S'ha postulat que una selecció positiva dels embrions lliures de aneuploïdies (és a dir, euploides) hauria d'augmentar la taxa d'embaràs dels embrions transferits al pacient. Publicacions recents, però, han demostrat que encara que es seleccionin els embrions euploides, la taxa d'embaràs no millora significativament, essent al voltant del 13%, mentre que en pacients als quals no s'aplica el DGP és del 30%. Un dels motius per aquest reduït èxit bé pot ser la tècnica utilitzada per realitzar el cribatge de aneuploïdies, la FISH, que limita l'estudi a només nou dels 23 cromosomes de l'embrió, quedant doncs més de la meitat sense diagnosticar. Per tant...

‣ Impacto do rastreamento clínico e genético para neoplasia endócrina múltipla tipo 1; The impact of clinical and genetic screenings on the management of the multiple endocrine neoplasia type 1

Lourenço-Jr, Delmar Muniz; Toledo, Rodrigo Almeida; Coutinho, Flavia Lima; Margarido, Leontina Conceição; Siqueira, Sheila Aparecida Coelho; Santos, Marcelo Augusto Cortina Gonçalves dos; Montenegro, Fabio Luiz de Menezes; Machado, Marcel Cerqueira Ce
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; Formato: application/pdf
Publicado em 01/01/2007 Português
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OBJETIVOS: Realizar rastreamentos clínico e gênico para Neoplasia Endócrina Múltipla tipo 1 (NEM1) e analisar seu impacto no seguimento clínico desses pacientes no Hospital das Clínicas, SP. MÉTODOS: O diagnóstico clínico de NEM1 foi realizado de acordo com o Consenso sobre neoplasias endócrinas múltiplas. A análise genética para identificação de mutações foi realizada por sequenciamento automático de todas as regiões codificadoras e fronteiras exon/intron do gene MEN1. Os casos afetados foram sub-divididos em 3 grupos e analisados separadamente: casos-índices (grupo I), familiares diagnosticados clinicamente (grupo II) e genicamente (grupo III). RESULTADOS: Um total de 154 casos participou desse estudo, sendo 52 diagnosticados com NEM1: 13 do grupo I, 28 do grupo II e 11 do grupo III. A idade média ao diagnóstico no grupo III (27 anos) foi significativamente menor que a dos grupos I (39,5 anos; p = 0,03) e II (42,4 anos; p = 0,01). A maioria dos pacientes dos grupos I e II apresentou 2 ou 3 tumores, enquanto que 81,8% dos casos do grupo III apresentavam 1 ou nenhum tumor relacionado à NEM1. Além disto, 45,4% dos casos do grupo III eram assintomáticos, não sendo observados nenhuma metástase ou óbito. Os demais 102 familiares sob-risco estudados não herdaram mutação MEN1 e foram excluídos do rastreamento clínico. Um caso de fenocópia NEM1 foi também localizado. DISCUSSÃO: Nossos dados demonstraram importantes benefícios no seguimento dos pacientes NEM1...

‣ Genetic testing for HFE hemochomatosis in Australia: The value of testing relatives of simple heterozygotes

Cavanaugh, Juleen A; Wilson, Susan; Bassett, Mark L
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
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Background: It is unclear whether screening of relatives of C282Y and H63D heterozygotes (other than compound heterozygotes) for hemochromatosis will detect sufficient numbers of cases to justify introduction of this screening strategy. Methods: Conditional probabilities were determined using published Australian allele frequencies and penetrance data to determine the detection rate of hemochromatosis by testing the siblings and offspring of heterozygotes (subjects with only one HFE mutation). Results: The number of individuals who are at risk of developing increased body iron stores because of HFE mutations is substantially higher (1 in 80) than previously estimated. In addition, 33% of the Australian population are heterozygous for either C282Y or H63D. Based on population estimates, the relative risk to the offspring of C282Y and H63D heterozygotes of developing increased iron stores is 4.1 and 1.5, respectively, while the relative risk to each sibling is 2.3 and 1, respectively. The risk of developing clinical features of hemochromatosis or hepatic fibrosis is likely to be substantially lower. Conclusions: Although the detection rate from testing the families of unaffected heterozygotes is low, this can be justified as a clinically useful screening strategy. At the present time this strategy should be restricted to first-degree relatives of heterozygotes. Further studies are recommended to determine if cascade genetic screening is a cost-effective alternative to general population screening.

‣ Incidental findings, genetic screening and the challenge of personalisation

Petrini,Carlo; Alleva,Enrico
Fonte: Istituto Superiore di Sanità Publicador: Istituto Superiore di Sanità
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/12/2014 Português
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Genetic tests frequently produce more information than is initially expected. Several documents have addressed this issue and offer suggestions regarding how this information should be managed and, in particular, concerning the expedience of revealing (or not revealing) it to the persons concerned. While the approaches to the management of these incidental findings (IFs) vary, it is usually recommended that the information be disclosed if there is confirmed clinical utility and the possibility of treatment or prevention. However, this leaves unsolved some fundamental issues such as the different ways of interpreting "clinical utility", countless sources of uncertainty and varying ways of defining the notion of "incidental". Guidelines and other reference documents can offer indications to those responsible for managing IFs but should not be allowed to relieve researchers and healthcare professionals of their responsibilities.