The introduction of cell-free DNA (cfDNA) screening for the most common fetal aneuploidies (trisomy 21, 18 and 13) has impacted prenatal testing, and is rapidly changing the standard care in obstetrics. The term NIPT (Non-Invasive Prenatal Testing) has been used to refer to this test and became very recognized. NIPT has been reducing the need for invasive procedures and the associated risk of procedure-related pregnancy loss. Although there are other methodologies that can be used in NIPT, read counting derived from massively parallel sequencing has become the method of choice in several medical centers, and most clinical validation studies come from this approach. Because no distinction is made between maternal and fetal sequences in the massively parallel sequencing, and considering that the largest fraction of cfDNA consists of maternal instead of fetal DNA fragments, imbalances in the maternal genome usually skew the statistical parameters, consequently impairing the accuracy of fetal aneuploidy detection. Although this is not the primary aim of NIPT, studies have demonstrated that the analysis and interpretation of maternal DNA copy number variations (CNVs) are warranted because some in fact can be clinically relevant, like the identification of presymptomatic maternal cancers. Nonetheless, the maternal CNVs reported so far in NIPT were large events, and current analyses do not interrogate small CNVs. Thus, the main objective of this project is to investigate the minimum size that allows accurate detection of maternal copy number changes from NIPT results, evaluating its potential clinical impact in diseases. Importantly, the knowledge gathered in this project can be widely apply to a range of clinical and research situations that involve DNA copy number estimation and mosaicism.
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