Abstract
BackgroundNon-invasive prenatal testing (NIPT) has been widely adopted for the detection of fetal aneuploidies and microdeletion syndromes, nevertheless, limited clinical utilization has been reported for the non-invasive prenatal screening of monogenic diseases. In this study, we present the development and validation of a single comprehensive NIPT for prenatal screening of chromosomal aneuploidies, microdeletions and 50 autosomal recessive disorders associated with severe or moderate clinical phenotype.ResultsWe employed a targeted capture enrichment technology powered by custom TArget Capture Sequences (TACS) and multi-engine bioinformatics analysis pipeline to develop and validate a novel NIPT test. This test was validated using 2033 cell-fee DNA (cfDNA) samples from maternal plasma of pregnant women referred for NIPT and paternal genomic DNA. Additionally, 200 amniotic fluid and CVS samples were used for validation purposes. All NIPT samples were correctly classified exhibiting 100% sensitivity (CI 89.7–100%) and 100% specificity (CI 99.8–100%) for chromosomal aneuploidies and microdeletions. Furthermore, 613 targeted causative mutations, of which 87 were unique, corresponding to 21 monogenic diseases, were identified. For the validation of the assay for prenatal diagnosis purposes, all aneuploidies, microdeletions and point mutations were correctly detected in all 200 amniotic fluid and CVS samples.ConclusionsWe present a NIPT for aneuploidies, microdeletions, and monogenic disorders. To our knowledge this is the first time that such a comprehensive NIPT is available for clinical implementation.
Highlights
Non-invasive prenatal testing (NIPT) has been widely adopted for the detection of fetal aneuploidies and microdeletion syndromes, limited clinical utilization has been reported for the non-invasive prenatal screening of monogenic diseases
The fetal risk for aneuploidies and microdeletions is provided based on the analysis of cell-free fetal DNA (cffDNA) present in maternal plasma, whilst the fetal risk for the autosomal recessive monogenic diseases is determined based on Mendelian law of inheritance by combining maternal and paternal carrier status information using cell free maternal DNA and paternal DNA respectively. The workflow of this novel comprehensive NIPT prenatal screening test for aneuploidies of 13, 18, 21, X, Y, four microdeletion syndromes and 50 single gene diseases, followed by prenatal diagnosis for these disorders in case of high risk pregnancy is described in Additional file 1
In the 2033 samples analyzed with this single comprehensive NIPT, we identified all samples correctly, exhibiting 100% sensitivity (CI 89.7–100%) and 100% specificity (CI 99.8–100%) for chromosomal aneuploidies and microdeletion syndromes
Summary
Non-invasive prenatal testing (NIPT) has been widely adopted for the detection of fetal aneuploidies and microdeletion syndromes, limited clinical utilization has been reported for the non-invasive prenatal screening of monogenic diseases. Different methods have been applied for the detection of fetal aneuploidies, mainly employing whole genome or targeted approaches combined with Generation Sequencing (NGS). The success of such methods has been highlighted in several clinical validation studies that demonstrate the ability for high aneuploidy detection rates [2,3,4,5,6,7,8,9]. In the absence of specific markers, NIPT can be used for sex chromosomal aneuploidies and for select microdeletion syndromes [10]
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