Opportunities and challenges in prenatal diagnosis : towards personalized fetal genetics

In this thesis we studied the efficacy and utilization of prenatal screening and prenatal diagnosis in the Netherlands and the increasing options for prenatal genetic diagnosis in general. In chapter 1 background information on prenatal screening and diagnosis in pregnancies conceived through artificial reproductive technology and on noninvasive prenatal diagnosis is given. Chapter 2 describes the study of a population-based cohort of 10,706 invasive prenatal procedures, analyzing trends in invasive prenatal diagnosis from January 2000 to December 2009. Our findings imply that in order to further increase the efficacy of invasive prenatal diagnosis in the Netherlands, advanced maternal age as indication for invasive testing should be abolished. In chapter 3 we present a follow-up study of all women who had a first trimester combined test performed during four and a half years after the start of the national screening program (n = 20,215). We concluded that pregnant women <36 years and women ≥ 36 years make different choices when confronted with similar Down syndrome risk estimates. These differences are likely to be due to the different manner in which the first trimester combined testing and invasive testing are being offered to these two age groups in the Netherlands. In chapter 4 we studied the hypothesis that the increased incidence of confined placental mosaicism (CPM) in IVF pregnancies, compared to spontaneous conceptions, might account for the poorer perinatal outcomes as observed in IVF singletons. This was done by comparing the incidence of CPM determined in 20,885 CVS procedures (235 IVF/ICSI; 20,650 controls), which were performed on the indication advanced maternal age, between IVF/ICSI pregnancies and spontaneous conceptions. The incidence of CPM was found not to be increased in IVF pregnancies compared with spontaneous conceptions. In chapter 5 we summarize the outcome of studies on prenatal array-CGH and SNP array and the clinical relevance of differences in detection rate and range as compared to standard karyotyping. Given the higher yield of array based techniques, compared to karyotyping, a greater detection rate of genomic anomalies in the prenatal setting is expected to facilitate prenatal diagnosis and parental counseling. The opportunities to establish a prenatal monogenic diagnosis by DNA-analysis have increased. In chapter 6 we show that with the rapid identification of new genes, the shortened turnaround time of DNA-analysis for monogenic disorders, and the increasing availability of NGS, prenatal detection of a causative mutation is feasible. In chapter 6a we report on novel inherited MYH7 mutations, which were detected in two unrelated fetuses and several family members. In chapter 6b prenatal detection of a de novo mutation in COL4A1 is reported in a fetus with the combination of a supratentorial hemorrhage and a cerebellar lesion observed with prenatal ultrasound and MRI. In chapter 7 opportunities and challenges in the field of prenatal genetic diagnosis are discussed. With the continuously expanding possibilities to diagnose fetal conditions, technically all genetic variations can become the target of prenatal testing. There are, however, still various challenges on the road towards personalized fetal genetics.