Non Invasive Prenatal Diagnosis of Down Syndrome

Abstract

Down syndrome (trisomy 21), which has an incidence of 1 in 800 live births, is considered to be the most frequent etiology of mental retardation and it is the predominant reason for women seeking prenatal diagnosis [Driscoll & Gross, 2009]. Trisomy 21 is used as a benchmark because it is the most common aneuploidy compatible with life and is associated with mental retardation and serious congenital anomalies. Currently used screening tests for aneuploidy are based on the assessment of fetal sonographic markers and/or the evaluation of biochemical markers in the maternal circulation during the first and second trimester. Screening test based on the combination of nuchal translucency assessment and biochemical markers at 11+0-13+6 weeks of gestation may detect 90-94% of pregnancies affected by Down syndrome at a false positive rate of 5% [Kagan et al., 2008]. The current gold standard for diagnosis of trisomy 21 is provided by invasive sampling of fetal genetic material through chorionic villus sampling (CVS) or amniocentesis followed by conventional cytogenetic or DNA analysis; however, both procedures are associated with an increased risk of fetal loss of about 1% and therefore they are recommended for pregnancies considered to be at high risk of fetal trisomy 21 [Alfirevic et al., 2003]. Since 1997, when cell free fetal DNA in maternal circulation was discovered, the research interest has focused on the development of reliable techniques for non-invasive prenatal diagnosis (NIPD) that would allow the direct analysis of fetal genetic material based on the discovery of cell-free fetal (cff) DNA and RNA in the maternal circulation. Current investigation fields of NIPD include fetal Rhesus D genotype determination in RhD negative women, fetal sex determination for sex-linked disorders and the role of cffDNA in pregnancy disorders such as preeclampsia but the holy grail of NIPD remains the detection of fetal aneuploidies [Honda et al., 2002; Bianchi et al., 2005]. The direct analysis of circulating fetal DNA for the NIPD of chromosomal aneuploidies is mainly complicated by the presence of the coexisting background maternal DNA. NIPD will hopefully overcome the limitations of the currently used methods for diagnosing Down syndrome antenatally and make prenatal testing safer for pregnant women and their fetuses. However, irrespective of which strategy is selected for isolating or distinguishing fetal genetic material in maternal plasma, the small quantity of cffDNA and cff mRNA poses severe technical challenges; all these issues should be addressed before the clinical application of these methods as screening test with high sensitivity, specificity and reproducibility.