Made available in DSpace on 2014-06-11T19:32:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-02-02Bitstream added on 2014-06-13T20:48:03Z : No. of bitstreams: 1 martinhago_cd_dr_botfm_prot.pdf: 1810275 bytes, checksum: 5592d92db2f6fd8dea862970f2f6df15 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Cpdp - Centro Paulista de Pesquisa e Diagnostico / O diagnóstico genético pré-implantacional (PGD) é um procedimento o qual permite que embriões sejam testados perante uma doença genética antes de sua transferência para o útero materno, ou seja, antes... / Preimplantation genetic diagnosis (PGD) is a procedure that permits embryos to be tested for a possible genetic diseade before being transferred to the maternal uterus, i.e., before the beginning of pregnancy... (Complete abstract click electronic access below)

The purpose of this thesis is to query the legitimacy of offering preimplantation genetic diagnostic (PGD) testing against Down's syndrome on the basis of United Kingdom (UK) law and policies. I will argue that extending PGD testing for Down’s syndrome as a permissible use of this technology does not (straightforwardly) adhere with the Human Fertilisation and Embryology Authority (HFEA) Code of Practice's stated factors which are to be considered when assessing the appropriateness of PGD applications. Indeed, due consideration of the evidence given in the relevant literature about the capacities and quality of life possible for persons living with Down's syndrome would seriously call into question the validity of a positive judgment recommending PGD as a treatment service for Down's syndrome according to the current UK regulatory instruments. I end the thesis by considering why the HFEA's relatively recent decision to limit client access according to an exclusive list of "serious" and therefore "in principle" test-worthy genetic conditions—understood as legitimate applications for PGD—stands to entrench prejudice, stigma, social bias, and unfair discrimination against the disadvantaged social group of persons living with Down's syndrome.

京都大学 / 0048 / 新制・課程博士 / 博士(社会健康医学) / 甲第20057号 / 社医博第75号 / 新制||社医||9(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 山田 亮, 教授 小泉 昭夫, 教授 松田 文彦 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

Thesis (PhD)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: With the development and continued developing of medical technology, treatments become available without the time to reflect ethically on them. Given how fast things change in medical technology, it is important to constantly reflect anew. Ethical reflection, however, seems to be lagging far behind bio-technological developments. Pre-implantation Genetic Diagnosis (PGD) and Human Genetic Manipulation (GM) is fast becoming an everyday reality and must therefore be reflected upon. Few Christian bioethical studies have been done on the impact that this could have on the larger populace, especially the local population in South Africa, where only a small percentage would be able to access these possible treatments. This study is motivated by the quest of ethicists in general and Christian ethicists in particular, to respond adequately and appropriately to the challenges posed by bio-technological developments. The study will outline and discuss the various Christian perspectives on PGD and GM. It will be shown that most Christian responses to bio-technological matters are done from within the framework of the doctrine of creation. In response, this study will then discuss a trinitarian perspective on the confession of God as creator and investigate whether this perspective might advance and enrich, and even amend, the quests of Christians to formulate ethical responses to the challenges posed by PGD and GM. I have made the decision to focus, for the most part, only on the work of one theologian, and will therefore be applying the trinitarian doctrine of creation as found in the work of Jürgen Moltmann to the development of a Christian bioethical perspective. Seeing that Christian ethics in general is concerned with human dignity, social justice and wellbeing, as well as moral upliftment, the ethical implications of this type of medical technology in the South African context, with its uneven distribution of wealth and access to medical care, must also be addressed from the perspective of this study. In this regard, the concept of human beings created imago Dei (in the image of God), with inherent human dignity, is of particular importance. / AFRIKAANSE OPSOMMING: Met die ontwikkeling en voortdurende ontwikkeling van mediese tegnologie word behandelinge beskikbaar sonder dat daar tyd is om eties daaroor te reflekteer. Gegewe hoe vinnig dinge verander in mediese tegnologie is dit belangrik om voortdurend nuut te reflekteer. Pre-implantasie Genetiese Diagnose (PGD) en Menslike Genetiese Manipulasie (GM) is vinnig beter om ‘n alledaagse realiteit te word en daarom moet daar daaroor reflekteer word. Daar is min Christelike bio-etiese studies gedoen oor die impak wat dit op die groter samelewing kan hê, veral in die plaaslike bevolking van Suid-Afrika, waar slegs ‘n klein persentasie toegang tot hierdie moontlike behandelinge sal hê. Hierdie studie word gemotiveer deur die poging van etici in die algemeen en Christelike etici spesifiek, om behoorlik en toepaslik te reageer op die uitdagings wat bio-tegnologiese ontwikkelinge bied. Die studie sal die verskillende Christelike perspektiewe op PGD en GM uiteensit en bespreek. Daar sal aangedui word dat die meeste Christelike antwoorde op die bio-tegnologiese kwessies gedoen word binne die raamwerk van die skeppingsleer. In reaksie hierop sal hierdie studie dan 'n trinitariese perspektief op die belydenis van God as Skepper bespreek en ondersoek of hierdie perspektief die poging om ‘n Christelike etiese antword te formuleer op die uitdagings wat PGD en GM bied kan bevorder en verryk, en moontlik selfs wysig. Ek het die besluit geneem om hoofsaaklik net op die werk van een teoloog te fokus, en sal dus die trinitariese skeppingsleer soos gevind in die werk van Jürgen Moltmann toepas tot die ontwikkeling van 'n Christelike bio-etiese perspektief. Aangesien die Christelike etiek in die algemeen gemoeid is met menswaardigheid, maatskaplike geregtigheid en welstand, asook morele opheffing, moet die etiese implikasies van hierdie tipe mediese tegnologie in die Suid-Afrikaanse konteks, met sy ongelyke verspreiding van rykdom en toegang tot mediese sorg, ook aangespreek. In hierdie verband is die konsep van die mens geskep Imago Dei (na die beeld van God), met inherente menswaardigheid, van besondere belang.

IntroductionPreimplantation Genetic Diagnosis (PGD) was developed in the 1990s and has been used since to diagnose and discard embryos with genetic conditions or chromosomal abnormalities. CRISPR-Cas9 was discovered in 2012 and has been used in research, but has not become clinical practice on humans yet. CRISPR-Cas9 could potentially be applied to treat and prevent genetic disorders.AimThe aim was to investigate the ethical dilemmas of each method through a set of research questions. The ethics of applying PGD according to Swedish guidelines and applying CRISPR-Cas9 on humans was investigated.MethodologyThis was not a systematic literature review. Instead, articles have been selected based on their explanation of each method and uniqueness or volume of ethical arguments surrounding each method, that is of relevance for the discussed issues.ResultsArguments in favour of PGD addressed among other things the somatic and psychological health of future children and parents along with the economical benefits. Arguments against PGD addressed different dilemmas of discarding an embryo and thereby a future individual. Arguments against CRISPR-Cas9 addressed technical limitations, our limited knowledge of genetics and more. Arguments in favour addressed benefits in clinical medicine and research.ConclusionsPGD according to Swedish guidelines was found to be ethically acceptable, since its restrictive use that have not given room for ethically dubious applications. CRISPR-Cas9 was found not to be safe enough for human applications at this moment due to technical limitations. If these were to be solved, caution and restraint must be urged.

"Mémoire présenté à la Faculté des études supérieures en vue de l'obtention du grade de LLM en maîtrise option recherche axe Droit, Biotechnologies et Société" / Le diagnostic préimplantatoire (DPI), issu d'une alliance entre la procréation médicalement assistée et les techniques de diagnostic génétique, met à la disposition des êtres humains des conditions entièrement nouvelles pour le "contrôle de la qualité" des enfants. Sur la base d'un vaste ensemble de critères, telle choix du sexe ou l'élimination d'une maladie génétique, les parents peuvent désormais sélectionner leurs embryons créés par fécondation in vitro en fonction de leurs caractéristiques génétiques. Les applications du DPI suscitent toutefois de nombreuses questions. Pas surprenant que le DPI et ses différentes applications fassent l'objet d'un intense débat éthique; ils requièrent certes la mise en place d'un cadre normatif. En 2004, le Canada a finalement adopté la Loi concernant la procréation médicalement assistée et la recherche connexe (L.C. 2004, ch. 2). À titre de manipulation sur l'embryon, le DPI y est indirectement couvert. L'article 10 (2) établit en ce sens une condition générale concernant la modification, la manipulation, le traitement ou l'utilisation d'un embryon in vitro dont le régime de réglementation et d'autorisation en déterminera les limites. Nous pouvons à juste titre nous demander ce qu'il en sera dans le cas de chacune des applications du DPI. L'une d'entre elles, la sélection du sexe pour des raisons non médicales, est déjà prohibée en vertu du texte de loi. Que prévoiront les règlements pour les autres utilisations du DPI? Le gouverneur en conseil dispose du pouvoir pour désigner les catégories d'activités pouvant faire l'objet d'une autorisation ainsi que pour établir les modalités d'exercice de toute activité réglementée. De quelle nature seront ces règlements? Que doivent-ils ou peuvent-ils contenir? Je m'interroge sur le contrôle juridique des diverses applications de cette technique diagnostique. À cet égard, la France et le Royaume-Uni offrent des modèles normatifs fort intéressants pour le Canada. Au cours de cette analyse j'ai cherché à déterminer lequel de ces deux modèles est le plus adapté à la réalité canadienne en matière de procréation médicalement assistée et de DPI. J'ai d'autre part constaté que le choix d'un modèle dépend de notre position à l'égard de certaines questions éthiques telle l'importance de l'autonomie reproductive (i.e. la liberté de choix des embryons en fonction de critères établis par les individus). / Preimplantation genetic diagnosis (PGD), which results from an alliance between medically assisted reproduction and genetic diagnostic techniques, provides humans with an entirely new means of chiId "quality control." Based on a vast set of criteria, such as sex selection or the elimination of a genetic disorder, parents can now select embryos created via in vitro fertilization according to their genetic characteristics. These applications give rise to numerous questions. It is not surprising that PGD and its various applications are the subject of intense ethical debate; the implementation of a legislative framework is a definite necessity. ln 2004, Canada finally adopted the Act Respecting Assisted Human Reproduction and Related Research (S.C. 2004, ch. 2). PGD is indirectly covered under embryo manipulation. Section 10 (2) sets out general conditions concerning the modification, manipulation, treatment or use of an in vitro embryo-the limits of which are determined by the regulation and authorization framework. We may rightly ask what form this will take in each PGD application. One of them, sex selection for nonmedical reasons, is already prohibited in the text of the Act. What regulatory provisions will be made for other uses of PGD? The Governor-in-Council has the power to designate categories of activities that may be authorized and to establish conditions for the exercise of any regulated activity. What type of regulations will they be? What must they or should they contain? 1 have examined the judicial control of various applications of this diagnostic technique. Both France and the United Kingdom offer normative models of interest to Canada. During this analysis, 1 have endeavoured to determine which of these two models is most suited to the Canadian reality with respect to medically assisted reproduction and PGD. 1 thus noted that the choice of a model also depends on our position on certain ethical issues such as the importance of reproductive autonomy (i.e., freedom of choice of embryos according to criteria established by individuals).

Les maladies les plus fréquentes prédisposant au cancer colorectal sont le Syndrome de Lynch et la Polypose Adénomateuse Familiale. Les gènes du système MMR, le gène APC et le gène MUTYH sont respectivement responsables. Le conseil génétique est primordial pour une prise en charge optimale des patients et des familles. Les Comités d'Oncogénétique aident les professionnels de santé à décider d'une indication d'analyse génétique et au suivi des familles. Nous souhaitons évaluer et améliorer a qualité décision prise pour une famille à risque. Des décisions très disparates d'un cas familial à un autre équivalent ont été suspectées. A Lyon, nous avons créé une base de données pour analyser et contribuer cela. Résultat : 100% (33/33) des centres français de consultations principales d'oncogénétique ont décrit l'organisation de leurs COG: 76% développent un COG spécifique, 24% utilisent une concertation standard. Environ 3.75 spécialités médicales sont rassemblées par COG, dont des oncogénéticiens (100%), gastro-entérologues (76%), conseillers en génétiques (84%), chirurgiens (32%), et biologistes/anatomopathologistes (36%). Vingt pourcent des centres ayant une COG spécifique discutent tous leurs cas familiaux, 80% sélectionnent leurs dossiers. Dans notre région, un outil informatique a été élaboré et sera largement diffusé. Notre but étant de standardiser nos décisions et, catégoriser des groupes de patients/familles, pour standardiser la surveillance proposée chez les familles équivalentes. Une meilleure rationalisation de la prise en charge, du suivi des familles, et de la prévention est ici ciblée. / The most common diseases that predispose for colorectal cancers are Lynch Syndrome and Familial Adenomatous Polyposis. The genes of MMR system, the APC gene and the MUTYH gene are respectively responsible. Genetic counselling is imperative for an optimal care making for patients and at-risk families. Multidisciplinary committees (MDC) are organized so as to help healthcare professionals for gene analysis decision and families' follow-up. Our aim is evaluation and improvement of quality decision-making for at-risk families. A disparate distribution of decisions from one familial case to another equivalent one has been suspected and observed. In Lyon region we created a database to analyse that and contribute to harmonize the different participants' work in MDC. Results: the 33 French oncogenetic main consultation centers described the organization of their MDC. Answering rate reached 100%. Among these centers, 76% developed a specific MDC, whereas 24% used standard consultation. About 3.75 different medical specialities are gathered by MDC. Among them, there are oncogeneticists (100%), gastroenterologists (76%), genetic counsellors (84%), surgeons (32%), and biologists (36%). Twenty percent of centers having a specific MDC evaluate all their patient cases, whereas 80% select them. In Lyon region, a computerized tool has been elaborated and will be widely disseminated to every collaborating partners of our MDC. It will enable us to standardize our decision-making and, by comparing decisions through quality criteria, to differentiate and categorize some patients/families groups. A better rationalization of care management, families' follow-up and prevention is targeted.

Made available in DSpace on 2016-08-10T10:38:29Z (GMT). No. of bitstreams: 1 Fernanda Carla Stegani.pdf: 10431040 bytes, checksum: 2702ca1faeabb2d893b8f2971288b01e (MD5) Previous issue date: 2011-12-08 / The Intellectual Disability (ID) is defined as a disability characterized by significant limitations both in intellectual functioning and in the adaptive behavior and it is expressed in practical, social and conceptual skills, originating before the age of 18. It is one of the most common neuropsychiatric disorders in children and adolescents, with a 5% prevalence in our population. The Fragile X Syndrome (FXS) is the most frequent and best documented DI heritable in humans. The phenotype of FXS is associated with mutations in the gene FMR1 (Fragile X Mental Retardation-linked type 1) and it covers a broad spectrum of behavioral and physical involvement. It is caused by a CGG trinucleotide expansion in the first exon of the FMR1 gene located in the region Xq27.3 on the X chromosome Because of its phenotypic diversity, this disease has been under diagnosed in the pediatric population. Among the techniques used for molecular diagnosis of FXS, the MLPA (Multiplex Ligation-dependent Probe Amplification) has been considered promising. In this context, this study aimed to validate the molecular diagnosis of patients suspected of FXS in the Laboratory of Cytogenetics and Molecular Genetics (Lagene) by the MLPA technique. We selected 33 patients referred by medical from public health to Lagene with clinical of FXS. To perform the analysis by MLPA the Salsa MLPA P106-B1 MRX kit was used. The amplificons were obtained only for 15% of the patients. The MLPA kit used did not detect changes in the copy number of the FMR1 gene in any examined patient, being useful the need of other molecular methods to confirm the diagnosis of FXS. Thus, we concluded that such MLPA kit was not useful to detect specific changes in the copy numbers of the FMR1 gene. So the Salsa MLPA Kit P106-B1 MRX should not be used to the trial of patients with FXS. / A Deficiência Intelectual (DI) é definida como uma incapacidade caracterizada por limitações significativas, tanto no funcionamento intelectual quanto no comportamento adaptativo e está expressa nas habilidades práticas, sociais e conceituais, originando-se antes dos 18 anos de idade. É um dos transtornos neuropsiquiátricos mais comuns em crianças e adolescentes, com taxa de prevalência de 5% na população brasileira. A Síndrome do X-Frágil (SXF) é a forma mais frequente, mais pesquisada e melhor documentada de DI herdável em seres humanos. O fenótipo da SXF está associado a mutações no gene FMR1 (Fragile Xlinked Mental Retardation type 1) e abrange um amplo espectro de envolvimento físico e comportamental. É causada por uma expansão de trinucleotídeos CGG no primeiro éxon do gene FMR1 localizado na região Xq27.3 no cromossomo X. Em função de sua diversidade fenotípica, esta doença tem sido subdiagnosticada na população pediátrica. A importância do reconhecimento clínico e diagnóstico específico da SXF vem do fato de que teoricamente todos os casos são hereditários e familiais. Entre as técnicas moleculares utilizadas para o diagnóstico da SXF, a MLPA (Multiplex Ligation-dependent Probe Amplification) tem sido considerada promissora. Nesse contexto, este estudo teve como objetivo validar o diagnóstico genético-molecular de pacientes com suspeita da SXF no Laboratório de Citogenética e Genética Molecular (LaGene) da Secretaria Estadual de Saúde do Estado de Goiás, na cidade de Goiânia, pela técnica de MLPA. Foram selecionados 33 pacientes encaminhados pelo serviço médico da rede pública de saúde ao LaGene com indicação clínica de diagnóstico da SXF. Para realização da análise por MLPA foi utilizado o Kit: Salsa MLPA P106-B1 MRX. Foram obtidas amplificações de apenas 15% dos pacientes. O Kit utilizado não detectou alterações no número de cópias do gene FMR1 em nenhum paciente analisado, sendo necessário a utilização de outros métodos moleculares para confirmação do diagnóstico da SXF. Dessa forma, concluímos que o Kit utilizado não foi específico para detectar alterações no número de cópias do gene FMR1, não se mostrou sensível e específico na detecção de portadores da SXF, sendo considerado oneroso. Assim a técnica de MLPA, com o uso do Kit Salsa MLPA P106-B1 MRX , não deverá ser utilizada para se triar pacientes com suspeita da SXF.

O diabetes mellitus tipo MODY (maturity-onset diabetes of the young) é caracterizado por defeito na secreção de insulina, herança autossômica dominante, hiperglicemia de início precoce e anticorpos anti-células beta negativos. Até o momento, já foram descritas mutações em 14 genes diferentes. A confirmação do diagnóstico de MODY é feita por estudo genético-molecular, tradicionalmente pelo método de Sanger. Diante da grande heterogeneidade genética de MODY, acrescida da dificuldade de estudo de alguns genes por seu grande tamanho e ausência de hotspots, o sequenciamento em larga escala (SLE) mostra-se promissor para uma análise genética custo-efetiva na suspeita de MODY. No Brasil, existem poucos estudos genéticos de rastreamento de MODY e uma alta prevalência de casos sem mutações identificadas nos genes testados (MODY X). Os objetivos deste estudo foram: 1) analisar simultaneamente todos os genes associados a MODY em uma coorte de pacientes com suspeita clínica, utilizando um painel de SLE; 2) avaliar a patogenicidade das variantes alélicas identificadas de acordo com os critérios da Sociedade Americana de Genética Médica (ACMG). Foram selecionados 80 casos com fenótipo de MODY e análise prévia negativa dos 2 genes mais prevalentes, GCK e HNF1A, pelo método de sequenciamento de Sanger. Estes casos foram analisados pelo método de SLE, direcionado para regiões gênicas alvo, por meio de um painel customizado, com sequenciamento simultâneo de 51 genes nucleares e do genoma mitocondrial. As mutações identificadas foram correlacionadas com o fenótipo e foi realizada a segregação familiar. Uma cobertura de no mínimo 20x foi obtida em 98% das regiões alvo. Dos 80 pacientes avaliados, foram detectadas variantes patogênicas/potencialmente patogênicas em 16 casos (20%), confirmando o diagnóstico genético de MODY. Em 15 dos 80 pacientes foram identificadas 16 variantes de significado incerto, restando ainda 42 casos com diagnóstico molecular não esclarecido. Dos 16 casos confirmados geneticamente: 6 foram no gene GCK, 1 no HNF1A, 1 no HNF4A, 1 no HNF1B, 6 em genes raros associados a MODY (1 no ABCC8, 1 no KCNJ11, 1 no PDX1, 2 no PAX4, 1 no NEUROD1), e 1 no NEUROG3, gene associado a diabetes neonatal. Dentre estas 16 variantes, 2 não haviam sido descritas previamente. As 6 mutações no GCK não tinham sido detectadas na análise prévia por: a) 4 casos falso negativos no sequenciamento por Sanger (3 devido ao fenômeno genético de allelic dropout e 1 por erro na leitura do eletroferograma); b) 2 erros na hipótese clínica inicial do subtipo de MODY (baseada no padrão glicêmico e na resposta terapêutica dos pacientes), levando ao sequenciamento prévio de outro gene. A variante no HNF1A não foi detectada previamente por erro na leitura do eletroferograma (caso falso negativo no Sanger). Uma variante foi identificada no gene HNF4A, que não tinha sido sequenciado anteriormente e apresenta fenótipo semelhante ao do HNF1A. O paciente com variante no HNF1B não apresentava relato prévio de cistos renais ou malformações genito-urinárias e por isso não tinha sido considerada a hipótese clínica de MODY5. Além disso, o SLE confirmou o diagnóstico genético de 6 pacientes com variantes em genes de MODY considerados raros, que habitualmente não são sequenciados na rotina de Sanger e ainda detectou uma variante em um gene de diabetes neonatal (sendo necessário maiores estudos para estabelecer uma relação causal com MODY). Em 13 dos 16 casos índices diagnosticados, os familiares encontravam-se disponíveis para exame genético e a co-segregação foi concordante em 8 famílias. Todos os probandos avaliados apresentavam características clínico-laboratoriais típicas de MODY. Os achados deste estudo mostraram que o SLE foi capaz de aumentar a acurácia no diagnóstico de MODY, permitindo a confirmação molecular de 20% dos casos antes negativos e reduzindo, assim, o número de casos MODY X no Brasil. A abordagem genética por painel de SLE para diagnosticar casos com suspeita clínica de MODY mostrou-se promissora para elucidar as bases genéticas desse tipo de diabetes monogênico / Diabetes mellitus type MODY (maturity-onset diabetes of the young) is characterized by defects in insulin secretion, autosomal dominant inheritance, early onset of hyperglycemia, and negative anti-beta cell antibodies. To date, mutations in 14 genes are associated with MODY. The definitive diagnosis relies on genetic tests, traditionally by Sanger sequencing. However, given the genetic heterogeneity of this condition, added to the difficulty of studying some genes due to their large size and lack of hotspots, large-scale sequencing (LSS) seems promising for cost-effective genetic analysis on suspicion of MODY. In Brazil, there are few cohorts screened for MODY and a high prevalence of MODY X (unclear genetic diagnosis). This study aimed to analyze simultaneously all MODY genes in a cohort of clinically suspected patients using a LSS panel; and to evaluate the pathogenicity of identified allelic variants according to the criteria of the American College of Medical Genetics and Genomics (ACMG). We selected 80 subjects with MODY phenotype and negative previous analysis of the 2 most prevalent genes, GCK and HNF1A, by Sanger sequencing method. These cases were analyzed by LSS method, with simultaneous sequencing of target genes. We designed a customized panel, including 51 nuclear genes and the mitochondrial genome. The identified mutations were correlated to the phenotype and family segregation was evaluated. At least 20x coverage was obtained in 98% of the targeted regions. Of 80 evaluated subjects, pathogenic/probably pathogenic variants were detected in 16 cases (20%), confirming the genetic diagnosis of MODY. In 15 of 80 patients, 16 variants of uncertain significance were identified, remaining 42 cases with unexplained molecular diagnosis. Of the 16 genetically confirmed cases: 6 were in the GCK gene, 1 in HNF1A, 1 in HNF4A, 1 in HNF1B, and 6 in rare genes associated with MODY (1 in ABCC8, 1 in KCNJ11, 1 in PDX1, 2 in PAX4 and 1 in NEUROD1), and 1 in NEUROG3, a gene associated with neonatal diabetes. Of these 16 variants, 2 had not been previously described. Those 6 variants in GCK were not detected in the prior analysis because of: a) 4 false negative cases in Sanger sequencing (allelic dropout had occurred in 3 cases and one variant was overlooked, due to electropherogram interpretation failure); b) 2 errors in the initial clinical hypothesis of the MODY subtype (based on the glycemic pattern and therapeutic response), leading to the prior sequencing of another gene. The variant in HNF1A was not previously identified due to misinterpretation in electropherogram (Sanger false negative case). One variant were detected in the HNF4A gene, not formerly sequenced, and had a similar phenotype to that of HNF1A. The patient with HNF1B variant did not have a previous report of renal cysts or genito-urinary malformations and therefore the clinical hypothesis of MODY5 was not considered. In addition, LSS confirmed the genetic diagnosis of 6 patients harboring variants in MODY genes considered to be rare, which are not usually sequenced in the Sanger routine, and also detected one variant in a neonatal diabetes gene (further studies are necessary to establish a causal relationship with MODY). Relatives were available for genetic testing in 13 of these 16 index cases diagnosed and co-segregation was concordant in 8 families. All probands evaluated showed typical clinical and laboratory characteristics of MODY. These study findings showed that targeted-LSS could increase accuracy in MODY diagnosis, enabling molecular confirmation of 20% of previous negative cases and thus reducing the number of MODY X cases in Brazil. The genetic approach of LSS panel to diagnose cases with clinical suspicion of MODY has shown promise for elucidating the genetic basis of this type of monogenic diabetes

Le diagnostic préimplantatoire (DPI), issu d'une alliance entre la procréation médicalement assistée et les techniques de diagnostic génétique, met à la disposition des êtres humains des conditions entièrement nouvelles pour le "contrôle de la qualité" des enfants. Sur la base d'un vaste ensemble de critères, telle choix du sexe ou l'élimination d'une maladie génétique, les parents peuvent désormais sélectionner leurs embryons créés par fécondation in vitro en fonction de leurs caractéristiques génétiques. Les applications du DPI suscitent toutefois de nombreuses questions. Pas surprenant que le DPI et ses différentes applications fassent l'objet d'un intense débat éthique; ils requièrent certes la mise en place d'un cadre normatif. En 2004, le Canada a finalement adopté la Loi concernant la procréation médicalement assistée et la recherche connexe (L.C. 2004, ch. 2). À titre de manipulation sur l'embryon, le DPI y est indirectement couvert. L'article 10 (2) établit en ce sens une condition générale concernant la modification, la manipulation, le traitement ou l'utilisation d'un embryon in vitro dont le régime de réglementation et d'autorisation en déterminera les limites. Nous pouvons à juste titre nous demander ce qu'il en sera dans le cas de chacune des applications du DPI. L'une d'entre elles, la sélection du sexe pour des raisons non médicales, est déjà prohibée en vertu du texte de loi. Que prévoiront les règlements pour les autres utilisations du DPI? Le gouverneur en conseil dispose du pouvoir pour désigner les catégories d'activités pouvant faire l'objet d'une autorisation ainsi que pour établir les modalités d'exercice de toute activité réglementée. De quelle nature seront ces règlements? Que doivent-ils ou peuvent-ils contenir? Je m'interroge sur le contrôle juridique des diverses applications de cette technique diagnostique. À cet égard, la France et le Royaume-Uni offrent des modèles normatifs fort intéressants pour le Canada. Au cours de cette analyse j'ai cherché à déterminer lequel de ces deux modèles est le plus adapté à la réalité canadienne en matière de procréation médicalement assistée et de DPI. J'ai d'autre part constaté que le choix d'un modèle dépend de notre position à l'égard de certaines questions éthiques telle l'importance de l'autonomie reproductive (i.e. la liberté de choix des embryons en fonction de critères établis par les individus). / Preimplantation genetic diagnosis (PGD), which results from an alliance between medically assisted reproduction and genetic diagnostic techniques, provides humans with an entirely new means of chiId "quality control." Based on a vast set of criteria, such as sex selection or the elimination of a genetic disorder, parents can now select embryos created via in vitro fertilization according to their genetic characteristics. These applications give rise to numerous questions. It is not surprising that PGD and its various applications are the subject of intense ethical debate; the implementation of a legislative framework is a definite necessity. ln 2004, Canada finally adopted the Act Respecting Assisted Human Reproduction and Related Research (S.C. 2004, ch. 2). PGD is indirectly covered under embryo manipulation. Section 10 (2) sets out general conditions concerning the modification, manipulation, treatment or use of an in vitro embryo-the limits of which are determined by the regulation and authorization framework. We may rightly ask what form this will take in each PGD application. One of them, sex selection for nonmedical reasons, is already prohibited in the text of the Act. What regulatory provisions will be made for other uses of PGD? The Governor-in-Council has the power to designate categories of activities that may be authorized and to establish conditions for the exercise of any regulated activity. What type of regulations will they be? What must they or should they contain? 1 have examined the judicial control of various applications of this diagnostic technique. Both France and the United Kingdom offer normative models of interest to Canada. During this analysis, 1 have endeavoured to determine which of these two models is most suited to the Canadian reality with respect to medically assisted reproduction and PGD. 1 thus noted that the choice of a model also depends on our position on certain ethical issues such as the importance of reproductive autonomy (i.e., freedom of choice of embryos according to criteria established by individuals). / "Mémoire présenté à la Faculté des études supérieures en vue de l'obtention du grade de LLM en maîtrise option recherche axe Droit, Biotechnologies et Société"