Methylome analysis of cfDNA: novel applications

Cell-free DNA (cfDNA) methylation analyses are increasingly being implemented for noninvasive screening, diagnosis and monitoring of physiological and pathological conditions. Here, I propose to expand these applications by focussing on 3 groups: healthy individuals, pregnant women and twins. First, I will assess intra-individual variation in cfDNA methylation by generating longitudinal and age-specific methylome data from healthy individuals, thus providing essential insights into the physiological variability and dynamics of cfDNA. In addition, the host lab developed a cfDNA methylation signature to predict early-onset preeclampsia presymptomatically in the first trimester of pregnancy. I will test if this signature also predicts late-onset preeclampsia. Next, I will develop a cfDNA methylation-based test to detect vanishing twins. This will provide not only basic knowledge but also a better interpretability of non-invasive prenatal tests. Lastly, I will assess if vanishing twin survivors carry a specific DNA methylation imprint, and test if that imprint elucidates the etiology of oculo-auriculo-vertebral-spectrum, a poorly understood, non-genetic developmental disorder. Gains to be expected from this project include early detection of preeclampsia and vanishing twins, thus reducing healthcare costs. In addition, charting cfDNA methylome variation will provide valuable information for screening programs and more tailored monitoring regimes in the near future.