京都大学 / 新制・課程博士 / 博士(医学) / 甲第24087号 / 医博第4863号 / 新制||医||1059(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 近藤 尚己, 教授 山本 洋介, 教授 辻川 明孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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No / WHO advice suggests a family-centred approach for managing the elevated risk of recessively inherited disorders in consanguineous communities, whilst emerging policy recommends community engagement as an integral component of genetic service development. This paper explores the feasibility of the family-centred approach in the UK Pakistani origin community. The study took place within a context of debate in the media, professional and lay circles about cousin marriage causing disability in children. Using qualitative methods, a total of six single-sex focus group discussions (n = 50) were conducted in three UK cities with a high settlement of people of Pakistani origin. Tape-recorded transcripts were analysed using framework analysis. Kinship networks within Pakistani origin communities are being sustained and marriage between close blood relatives continues to take place alongside other marriage options. Study participants were critical of what was perceived as a prevalent notion that cousin marriage causes disability in children. They were willing to discuss cousin marriage and disability, share genetic information and engage with genetic issues. A desire for accurate information and a public informed about genetic issues was articulated whilst ineffective communication of genetic risk information undermined professionals in their support role. This study suggests a community that is embracing change, one in which kinship networks are still active and genetic information exchange is taking place. At the community level, these are conditions supportive of the family-centred approach to genetic testing and counselling.

The effect of psychosocial information resources on the psychological impact of genetic testing for patients Background: The genetic testing process has been shown to have a profound psychosocial impact on patients and families, yet research suggests that there is a lack of practical and helpful psychosocial information written to support decision-making. Ideally, this should be available for use both before and after genetic testing and should be easily accessed through genetic clinics. The development of pre-written leaflets or on-line resources which draw on the experiences and advice of families who have been through similar experiences, and are readily available through genetic clinics, might be one way of helping families make necessary adjustments. Aim: The aim of this study was to develop information resources for a) people undergoing carrier testing, and b) parents of children with undiagnosed conditions, and to pilot the use of these resources with service users. Methods: A systematic literature review was conducted to identify key themes to inform the content of the resources. To build on these findings, in-depth interviews were conducted with 11 people who had undergone carrier testing and 14 parents of children without a diagnosis. Interview data were analysed using the grounded theory method. A grey literature search of existing patient information was also conducted. These three phases informed the content of information resources. The development process also included input from genetic specialists, patient group representatives and interviewees. Finally, a pilot study was conducted through three genetic centres to assess the feasibility of a study testing the use of the resources. Findings: The participants in this study were striving for empowerment: carriers sought reproductive empowerment; parents developed empowerment strategies in order to advocate for their child. Moreover, a theory named ‘reconstructing the meaning of being a parent’ was constructed to describe the experience of parenting a child for whom no clear care pathway existed. The importance of providing timely information was identified as being a key factor in supporting parents during their search for a diagnosis. A new model was built to summarise the overarching experience of participants in this study. Conclusions: Empowerment was identified as a dynamic and multi-faceted construct. Health professionals and support groups can help facilitate the empowerment process through the provision of timely psychosocial information. This is particularly important in an age when patients are expected to take greater control than ever before over decisions affecting their healthcare.

Submitted by admin tede (tede@pucgoias.edu.br) on 2016-08-18T13:16:28Z No. of bitstreams: 1 Roberto Carlos Gomes da Silva.pdf: 3176847 bytes, checksum: b508a4a3eb30a62abd86ea9330f277e4 (MD5) / Made available in DSpace on 2016-08-18T13:16:28Z (GMT). No. of bitstreams: 1 Roberto Carlos Gomes da Silva.pdf: 3176847 bytes, checksum: b508a4a3eb30a62abd86ea9330f277e4 (MD5) Previous issue date: 2008-04-09 / Since DNA structure was described, several studies have been carried out in genetics that promoted a revolution in the practice of medicine. Human syndromes that were practically undiagnosed became easily diagnosed with molecular tools. However, most of the genetic diseases remain under diagnostic obscurity, increasing health concerns for affected people and public demand for preventive health care such as the case of Fragile-X Syndrome, the most common heritable form of mental retardation in humans. FXS is caused by an expansion of CGG repeat sequence in the promoter region of FMR1 gene, located in Xq27.3. Both men and women are affected by FXS and pre-mutation can expand to a full mutation in the next generation. Under full mutation status ( 200 repeats) the gene is silenced and FMRP protein is not produced causing mental retardation, speech delay, and behavior problems, the most frequent symptoms in FXS. Prevalence of FXS is estimated in 1:4000 and 1:8000 and of carriers in the general population as 1:813 and 1:259 for men and women, respectively. Because of FXS potential to affect subsequent generations it is crucial to properly diagnose the syndrome. Laboratory analysis of DNA from FXS, using PCR or Southern Blotting, allows reaching the diagnosis in 99% of cases carrying mutated genes. However, to date the Brazilian Public Health System does not recognize the molecular methods to reach complete diagnostic in FXS. Early diagnose would allow fore more appropriate and efficient therapy approaches, favoring satisfactory development of all affected people, minimizing their suffering and the burden on their families, increasing, on the other hand, their quality of life which should go beyond survival. / A partir da descrição da estrutura do DNA, várias pesquisas foram desenvolvidas na área da Genética, promovendo uma revolução na prática da medicina. Síndromes, antes difíceis ou até impossíveis de serem detectadas, com tecnologia e ferramentas moleculares, tornaram-se facilmente diagnosticadas. Entretanto, diversas doenças ainda persistem na obscuridade de diagnóstico e geram problemas de saúde pública como é o caso da Síndrome do X-Frágil (SXF), que é a causa mais comum de retardo mental masculino herdado, e que consiste na expansão do número de cópias de uma seqüência de bases CGG do DNA no gene FMR1, localizado no cromossomo Xq27.3. A SXF afeta tanto homens quanto mulheres e a pré-mutação poderá expandir-se à mutação completa nas próximas gerações. Os portadores da pré-mutação continuam produzindo a proteína FMRP e os portadores da mutação completa são afetados pela SXF, pois o gene FMR1 é silenciado, e a proteína não é produzida, causando retardo mental, problemas de linguagem e de comportamento. A prevalência da SXF é estimada em 1:4000 e 1:8000, e para portadores na população em geral é 1:813 e 1:259 para homens e mulheres respectivamente. A importância do reconhecimento clínico e diagnóstico da SXF vem do fato de que as gerações futuras poderão estar comprometidas. O estudo do DNA para X-frágil pela PCR e Southern blotting permite determinar com segurança superior a 99% quem é portador da pré-mutação do gene FMR1 e quem possui a mutação completa. Entretanto, o SUS não reconhece os métodos moleculares, apesar do diagnóstico permitir intervenções terapêuticas, com respostas bastante eficientes, favorecendo o desenvolvimento de modo integral das pessoas afetadas, minimizando seu sofrimento e de seus familiares, uma vez que a qualidade de vida deve ir além da sobrevivência.

For linkage region on chromosome 5, further fine mapping was performed on a total of three pedigrees. Linkage analysis revealed a maximum two point LOD score of 4.81 at marker D5S2505. Haplotype analysis narrowed the linkage region to 5p15.33-p15.2. Resequencing of five candidate genes, IRX2, IRX1, POLS, CCT5 and CTNND2 within the linkage region did not reveal any myopia mutation. They were therefore excluded as the myopia causative gene. Genotyping of 41 SNPs within this region in a Chinese cohort of 94 high myopia cases and 94 control subjects showed that the allele and genotypes distributions of rs370010 was significantly different between cases and controls (genotype P= 0.01176, allele P=0.00271 and trend P=0.00375). This SNP is located within a hypothetical gene LOC442129. After multiple testing corrections, none of the SNP remained significantly associated with high myopia. This is a novel myopia locus. Further work to identify the myopia gene in this region would involve candidate gene resequencing, family linkage analysis and gene-based SNPs association analysis. / High myopia is defined as refractive error below or equal to -6 dioptres (D). The prevalence of high myopia varies among different populations. The most common pathological structural abnormality in high myopia is the excessive lengthening of the posterior segment of the ocular globe. Apart from causing impaired vision, it may lead to severe ocular complications. The precise mechanistic role of genes and environmental factors in the development of high myopia is still uncertain. Studies of twins and families suggested that heredity is a major contributing factor. While no myopia gene has yet to be identified, 14 putative loci have been found on many chromosomes. In this study, we have utilized different approaches to map the myopia locus in the Chinese population. / In our family-based genome-wide scan program, the whole genome of Chinese high myopia pedigrees was screened by using microsatellite markers. Two point LOD scores > 1 were observed on chromosomes 12 and 5. Regions were further analyzed by fine mapping. For linkage region on chromosome 12, a maximum two point LOD score of 2.71 was obtained at marker D12S88 and suggested linkage region was narrowed at 12q21.31-q22 by haplotype analysis. Lumican located in this region was screened and no segregation of polymorphism was observed within the pedigree. The suggested locus in this study overlapped with the MYP3 but with a smaller interval than the one reported. Lumican was excluded to be the myopia gene in this locus. / In the candidate-gene program, the paired box gene 6 (PAX6) on 11p13, was first studied. Two dinucleotide repeats (AC)m and (AG)n in the promoter region were found to be highly polymorphic. Association was observed between these two repeats with high myopia in which patients had high repeat number in both (AC) m and (AG)n (p-value=0.0001317 and p-value=0.001). Our results indicated that the Chinese population does not show association between high myopia and polymorphisms in PAX6 coding region but the AC and AG dinucleotide repeats in the promoter region was significantly associated with high myopia. / Lam, Ching Yan. / "August 2007." / Source: Dissertation Abstracts International, Volume: 69-07, Section: B, page: 4103. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Leung Yuk Fai. / "June 2002." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 132-166). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Exome sequencing, the process of sequencing the set of all known exons simultaneously using next-generation sequencing technology, has dramatically changed the landscape of genetic research and genetic testing. The incredible volume of data produced by these experiments creates challenges in: 1) annotating the affects of observed variants, 2) filtering to remove noise, 3) identifying plausible disease-causing variants, and 4) validating experimental results. Here we will present a series of bioinformatic tools and techniques intended to address these challenges with exome sequencing and associated validation experiments. First, we will present the Automated Sequence Analysis Pipeline (ASAP), a tool for the efficient and automated management, detection and annotation of Sanger sequencing-based genetic testing and variant validation. This pipeline is extended to annotate exome-sequencing derived variants. Exome sequencing experiments produce a great number of variants that do not cause a patient's disease. One of the biggest challenges in exome sequencing experiments is sorting through these false positives to discover the true disease-causing variants. We have developed several techniques to aid in the reduction of these errors. The techniques described include: 1) the construction of a catalog of systematic errors by reprocessing thousands of publically available exomes, 2) a tool for the filtering of variants based on family structure and disease assumptions, and 3) a tool for discovering regions of autozygosity from the exomes of several affected patients in consanguineous pedigrees. Classes of variants that are undiscoverable using current analysis techniques gives rise to false negatives in exome sequencing experiments. We will present a tool, the Retrotransposon Insertion Detector for Exomes (RIDE) that uses the characteristic anomalies present in sequence alignments to detect the insertion of repetitive elements. The process of identifying a the cause of a patient's disease using exome sequencing data has been equated to finding a needle in a stack of needles. Only through the proper annotation of variants and the reduction of the error rates associated with exome sequencing experiments can this task be achieved in an efficient manner.

Lynch syndrome (LS) is the most prevalent cause of hereditary colorectal cancer (CRC) and confers high risks for several other types of cancer. Universal tumor screening (UTS) of all newly diagnosed patients with CRC can improve LS identification and decrease associated morbidity and mortality among patients and family members. However, for UTS to be effective, patients who screen positive must pursue genetic counseling and confirmatory germline testing (i.e., high patient reach). The purposes of this study were to characterize UTS programs, identify barriers and facilitators to implementation, document whether there have been negative outcomes, and determine institutional and implementation conditions that are associated with high and low patient reach. Using two conceptual frameworks, RE-AIM and Consolidated Framework for Implementation Research, a baseline survey was conducted of 25 representatives from different institutions performing UTS. Descriptive statistics were used to illustrate similarities and differences among programs. A multiple-case study was then conducted by extracting data from surveys and interviews of representatives from 15 different institutions where UTS programs had been operational for over 6 months and where aggregated patient outcome data were available. Qualitative comparative analysis was performed to make systematic cross-case comparisons and identify conditions uniquely associated with high or low patient reach. Data were triangulated to create models explaining how UTS implementation and system-level factors influence patient reach. Few patient concerns or negative outcomes were reported. UTS procedures and patient reach were highly variable. All 5 high-reach (H-R) centers have genetics professionals disclose positive screening results and either do not require a referral from another health care provider or have streamlined the referral process. Although 2 of the 5 mid-reach (M-R) centers also share these conditions, they have a less automated follow-up procedure and report difficulty contacting patients as a barrier. Both of the academic institutions with low patient reach (L-R) did not receive patient information that would allow them to follow-up on positive screening results. The three non-academic L-R institutions reported a high proportion of challenges to facilitators during implementation and did not have genetic professionals disclose positive screening results to patients. Implementing a combination of procedures to streamline UTS protocols and procedures, eliminate barriers to patient follow-through after a positive tumor screen, and incorporate a high level of involvement of genetic professionals in contacting patients and disclosing screening results are expected to lead to improvement in patient reach

This thesis explores the subject positions available to users of genetic tests for bipolar disorder in the United States. In advanced liberal societies, tests for genetic susceptibility to complex disorders may be promoted and used as means of performing responsible citizenship through the consumption of health care services. In the context of mental illness, however, key assumptions about the characteristics of consumers may not be met. The research found that because the category of “potential test user” substantially overlaps with the category of “mental health care user,” both the rationality and autonomy of these individuals is subject to question. Test users are framed in relational terms: as family members, as patients, and as consumers – but the last of these relational frames is considered problematic. Therefore, while the tests are framed as tools for proactive health management, responsibilities surrounding their use are largely allocated to family members and doctors.