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Cffdna) Enrichment for Non-Invasive Prenatal Testing (NIPT

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Cffdna) Enrichment for Non-Invasive Prenatal Testing (NIPT Cell-free fetal DNA (cffDNA) enrichment for non-invasive prenatal testing (NIPT): a comparison of molecular techniques by Kelly A Sillence A thesis submitted to the University of Plymouth in partial fulfilment for the degree of DOCTOR OF PHILOSOPHY (December 2015) School of Biomedical and Healthcare Sciences I Copyright Statement This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the author's prior consent. II Cell-free fetal DNA (cffDNA) enrichment for non-invasive prenatal testing (NIPT): a comparison of molecular techniques Kelly Sillence ABSTRACT Prenatal assessment of fetal health is routinely offered throughout pregnancy to ensure that the most effective management can be provided to maintain fetal and maternal well-being. Currently, invasive testing is used for definitive diagnosis of fetal aneuploidy, which is associated with a 1% risk of iatrogenic fetal loss. Developing non-invasive prenatal testing (NIPT) is a key area of research and methods to increase the level of cell-free fetal DNA (cffDNA) within the maternal circulation have been discussed to improve accuracy of such tests. In this study, three strategies; co-amplification at lower denaturation temperature polymerase chain reaction (COLD-PCR), inverse-PCR and Pippin Prep™ gel electrophoresis, were analysed to identify a novel approach to selectively enrich shorter cffDNA fragments from larger maternal cell-free DNA (cfDNA). The sensitivity of droplet digital PCR (ddPCR) against real-time PCR (qPCR) was compared for fetal sex and RHD genotyping. In addition RHD zygosity testing was carried out for non-maternal samples. Consequently, Pippin Prep™ gel electrophoresis was combined with ddPCR analysis for the NIPD of Down Syndrome (DS) in pseudo-maternal samples. The results revealed that the Pippin Prep™ gel electrophoresis enrichment approach successfully demonstrated 2-fold to 5-fold increases in the cffDNA fraction. However, further optimisation assays of COLD-PCR and inverse-PCR using actual maternal samples were required. The spike experiments for DS detection revealed that with the present assay III overrepresentation of the chromosome 21 target could be significantly detected for samples with ≥15% ‘cffDNA fraction’. In conjunction with the Pippin Prep™ enrichment method, this would have enabled assessment of all 10 maternal samples. Alternatively, fetal sex and RHD genotyping results determined that ddPCR provides a more sensitive platform compared to qPCR approaches, particularly for samples that express low cffDNA fractions (<2%). The ddPCR platform also proved to be a rapid and accurate system for the determination of RHD zygosity. This study highlights that ddPCR could be used as opposed to qPCR for accurate determination of fetal sex and RHD status. While sequencing approaches currently provide the most sensitive platforms for NIPT of fetal aneuploidy, high costs (>£400) prevent universal application. The combination of cffDNA enrichment with ddPCR analysis could provide a cheaper and more widely available platform for NIPD. However, further large scale validation studies using actual maternal samples are required. IV Table of Contents List of figures and tables…………………………………………………………………..1 Acknowledgements………………………………………………………………………10 Declaration……………………………………………………………………………….11 Conferences attended, academic prizes and publications………………………………..12 List of Abbreviations……………………………………………………………………..13 Dedication…………………………………………………………...…………………...17 Chapter 1 ....................................................................................................................... 18 Introduction......................................................................................................................18 1.1 Prenatal screening ............................................................................................... 19 1.1.1 Definitions.................................................................................................... 19 1.1.2 Prenatal screening for fetal aneuploidy........................................................ 21 1.1.2.1 Historical overview and current practice for prenatal screening for fetal aneuploidy ............................................................................................................... 21 1.1.2.2 Developments of Sonographic Markers ................................................... 28 1.1.2.3 Development of Serum/Plasma and Urine Biomarkers ........................... 33 1.1.2.4 NGS for NIPT of Fetal Aneuploidy ......................................................... 38 1.1.3 Prenatal screening for monogenic disorders ................................................ 41 1.2 Invasive testing .................................................................................................... 45 1.3 Prenatal diagnosis ................................................................................................ 47 1.3.1 Fetal cells ..................................................................................................... 47 1.3.2 Fetal RNA .................................................................................................... 49 1.3.3 Cell-free fetal DNA (cffDNA) ..................................................................... 51 1.3.3.1 Fetal sex determination ............................................................................ 55 1.3.3.2 Fetal RHD genotyping ............................................................................. 57 1.3.3.3 Determining fetal aneuploidy ................................................................... 62 1.3.3.3.1 Digital PCR ......................................................................................... 64 1.3.3.3.2 MPS .................................................................................................... 71 1.3.3.4 Determining fetal monogenic disorders ................................................... 80 1.3.3.5 cffDNA enrichment .................................................................................. 82 1.4 Ethical considerations ......................................................................................... 86 Chapter 2………………………………………………………………………………91 Materials and methods………..………………………………………………………...91 2.1 Sample collection ................................................................................................ 92 V 2.1.1 Pre-ordered samples ..................................................................................... 92 2.1.2 Human whole blood samples ....................................................................... 92 2.1.2.1 DNA extractions of whole blood samples................................................ 92 2.1.2.2 DNA extraction of buffy coat from whole blood samples ....................... 93 2.1.3 Pseudo-fetal DNA samples .......................................................................... 94 2.1.4 Pseudo-maternal samples ............................................................................. 96 2.1.5 Maternal samples ......................................................................................... 97 2.2 Primer Design ...................................................................................................... 98 2.2.1 Polymorphic STR amplicon (D21S1890) .................................................... 98 2.2.2 Non-polymorphic amplicon regions ............................................................ 99 2.3 Conventional and COLD PCR .......................................................................... 102 2.3.1 Conventional PCR ..................................................................................... 102 2.3.2 COLD-PCR ................................................................................................ 102 2.4 Agarose gel electrophoresis .............................................................................. 103 2.5 Gel Extraction ................................................................................................... 104 2.6 Assessment of DNA quality and concentration ................................................ 105 2.6.1 Quantification by UV spectrophotometry .................................................. 105 2.6.2 Quantification by fluorescence .................................................................. 105 2.6.3 DNA analysis ............................................................................................. 106 2.7 Real-time PCR (qPCR) ..................................................................................... 107 2.7.1 qPCR .......................................................................................................... 107 2.7.2 qPCR to determine critical denaturation temperature ................................ 108 2.7.3 Quantifying DNA targets using Cq values ................................................ 109 2.8 Inverse PCR....................................................................................................... 110 2.8.1 EcoR1 Restriction Digest to obtain purified RH fragment ........................ 110 2.8.2 Ligation using T4 DNA Ligase.................................................................. 112 2.8.3 Inverse PCR ............................................................................................... 113 2.8.4 Sequencing ................................................................................................
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