Evaluation of the possibility to detect fetal chromosome trisomies based on a defined set of single nucleotide polymorphisms for non-invasive prenatal testing

Abstract

Non-invasive prenatal testing (NIPT) of fetal aneuploidy using cell-free fetal (cffDNA) from mother’s blood sample has shown to be an accurate and reliable screening tool. The current NIPT protocols are based on targeted or whole genome sequencing, which demand resource-intensive bioinformatical capacity. The complexity of current NIPT technology is trustworthy but the comprehensive adaption of the application is still limited due to the high cost. Mother- and fetus-specific genotypes, according to the nature of cell-free DNA (cfDNA) during pregnancy, were simulated and used in further analysis. Simulations and theoretical calculations demonstrate the characteristic patterns of allelic ratios in case of normal number of chromosomes or trisomy where extra chromosome is inherited from mother or father. Here described analytical approach managed to identify fetal trisomy by comparing the allelic ratios of the risk chromosome with the expected allelic ratios using the t-test and hidden Markov model (HMM) analysis. An average, 3/4 of all highly polymorphic single nucleotide polymorphisms (SNPs) can be used in analysis based on comparison of the allelic ratios. As a result, at least 300 highly polymorphic SNPs over risk and reference chromosomes are needed to detect fetal trisomy using t-test alone. In addition, the HMM analysis can independently detect fetal trisomy and have the ability to distinguish the parental origin of trisomy. Based on the simulated data, the existence and the origin of fetal trisomy is theoretically detectable using a novel and highly quantitative SNP-based approach that is under development by our research group. However, further testing has to be carried out with the real data to confirm the theory.