The discovery of fetal-derived circulating nucleic acids in maternal plasma has opened up new opportunities for non-invasive prenatal diagnosis. This non-invasive means of obtaining fetal genetic materials is safer than invasive tissue-sampling procedures, which are associated with a small but finite chance of fetal loss. Over the past decade, the detection of fetal DNA in maternal plasma has evolved from dependency on discriminative genetic markers, such as Y-chromosome-specific loci or paternally-inherited polymorphisms, to detection of circulating RNA, fetal-specific methylation or by massively parallel sequencing. Fetal-specific methylation, or fetal epigenetic marker, does not require prior knowledge of the sex or polymorphic status of the fetus and thus can be applied in essentially all pergnancies. This thesis focuses on the development of this kind of marker for non-invasive monitoring and detection of pre-eclampsia and fetal aneuploidies. / The first part of this thesis describes the use of a reported fetal epigenetic marker, RASISF1A, to measure the fetal DNA concentrations in maternal plasma of pre-eclamptic subjects versus gestational-age-matched controls. The second part of this thesis describes a systematic search for potential epigenetic markers for pre-eclampsia and the second commonest fetal aneuploidy, trisomy 18. Numerous approaches for methylation profiling are described, such as methylation-specific polymerase chain reaction (MSP), bisulfite sequencing, a mass spectrometry-based platform (the Epityper assay), and methylated DNA immunoprecipitation coupled with tiling array analysis (MeDIP-chip). Using MeDIP-chip, I selected the most promising fetal epigenetic markers on chromosome 18, and further characterised their detection in maternal plasma. The final part of this thesis describes an approach called epigenetic-genetic (EGG) chromosome dosage for the detection of trisomy 18 based on those markers. I have demonstrated that it is feasible to detect fetal trisomy 18 by analysing maternal plasma in as early as the first trimester. / This thesis illustrates different strategies for methylation profiling and presented two examples of applying DNA methylation for the non-invasive prenatal assessment of pregnancy-associated disorders and fetal chromosomal aneuploidies. I envision that a similar strategy could be developed for other pregnancy-related diseases to broaden the application of epigenetic markers in non-invasive prenatal diagnosis. / Tsui, Wai Yi. / Adviser: Y.M. Dennis Lo. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 198-221). / 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, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344673 |
| Date | January 2010 |
| Contributors | Tsui, Wai Yi., Chinese University of Hong Kong Graduate School. Division of Chemical Pathology. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xviii, 221 leaves : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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