Cover Page
The handle http://hdl.handle.net/1887/37582 holds various files of this Leiden University dissertation.
Author: Oever, Jessica Maria Elisabeth van den
Title: Noninvasive prenatal detection of genetic defects
Issue Date: 2016-02-03
Noninvasive prenatal detection of genetic defects.
Proefschri ter verkrijging van
de graad van Doctor aan de Universiteit van Leiden, op gezag van Rector Magnifi cus prof. mr. C.J.J.M. Stolker,
volgens besluit van het College voor Promo es te verdedigen op woensdag 3 februari 2016
klokke 16.15 uur
door
Jessica Maria Elisabeth van den Oever geboren te Roosendaal
in 1980.
Promotor: Prof. dr. E. Bakker Co-promotor: Dr. E.M.J. Boon Leden promo ecommissie: Prof. dr. M.H. Breuning
Prof. dr. G.C.M.L. Page - Chris aens (UMCU, Utrecht) Prof. dr. D. Oepkes
Prof. dr. C.M.A. van Ravenswaaij - Arts (UMCG, Groningen)
The research described in this thesis was performed at the Laboratory for Diagnostic Genome Analysis of the Leiden University Medical Center.
The prin ng of this thesis was fi nancially supported by BIOKÉ, GC Biotech, NVOG and the De- partment of Clinical Gene cs, Leiden University Medical Center.
ISBN: 978-94-6295431-1
© 2016, Jessica van den Oever
Cover design and printed by: Uitgeverij BOXPress
Contents
List of abbrevia ons 4
Chapter 1: General introduc on 7
Chapter 2: mRASSF1A-PAP, a novel methyla on-based assay for the detec on of cell-free fetal
DNA in maternal plasma 23
Chapter 3: Single Molecule Sequencing of Free DNA from Maternal Plasma for Noninvasive
Trisomy 21 Detec on 39
Chapter 4: Successful Noninvasive Trisomy 18 Detec on Using Single Molecule Sequencing 55 Chapter 5: A novel targeted approach for noninvasive detec on of paternally inherited muta-
ons in maternal plasma 65
Chapter 6: Noninvasive prenatal diagnosis of Hun ngton Disease; detec on of the paternally inherited expanded CAG repeat in maternal plasma 81
Chapter 7: Discussion 93
Chapter 8: Summary 103
Samenva ng 107
References 111
Curriculum vitae 129
Publica ons and Presenta ons 133
Dankwoord 139
Appendix 1: Confi ned placental mosaicism 143 Appendix 2: Epigene c allelic ra o, haplotype ra o analysis and rela ve muta on dosage.
146 Appendix 3: Calcula ons for trisomy detec on 149
List of abbrevia ons
Cf(f)DNA Cell-free (fetal) DNA CPM Confi ned placental mosaicism CVS Chorionic villus sampling DMR Diff eren ally methylated region EAR Epigene c allelic ra o
FCT First trimester combined test HTT Hun ng n gene
LNA Locked nucleic acid LTC Long-term culture MP Micropar cle
MPS Massive parallel sequencing MSP Methyla on specifi c PCR NGS Next Genera on Sequencing NIPD Noninvasive prenatal diagnos cs NIPT Noninvasive prenatal tes ng NCV Normalized chromosome value NT Nuchal translucency
PE Paired-end
QF-PCR Quan ta ve fl uorescent PCR
(m)RASSF1A (methylated) Ras associa on (RalGDS/AF-6) domain fami- ly member 1, isoform or transcript variant A
RHD Rhesus D gene RMD Rela ve muta on dosage RSTD Rela ve sequence tag density SMS Single molecule sequencing SNP Single nucleo de polymorphism SRY Sex determining region Y STC Short-term culture T13 Trisomy 13, Patau syndrome T18 Trisomy 18, Edwards syndrome T21 Trisomy 21, Down syndrome TFM True fetal mosaicism WGS Whole genome sequencing
