Abstract
Cell-free fetal DNA fraction (FF) in maternal plasma is a key parameter affecting the performance of noninvasive prenatal testing (NIPT). Accurate quantitation of FF plays a pivotal role in these tests. However, there are few methods that could determine FF with high accuracy using shallow‐depth whole‐genome sequencing data. In this study, we hypothesized that the actual FF in maternal plasma should be proportional to the discrepancy rate between the observed genotypes and inferred genotypes based on the linkage disequilibrium rule in certain polymorphism sites. Based on this hypothesis, we developed a method named Linkage Disequilibrium information-based cell-free Fetal DNA Fraction (LDFF) to accurately quantify FF in maternal plasma. This method achieves a high performance and outperforms existing methods in the fetal DNA fraction estimation. As LDFF is a gender-independent method and developed on shallow-depth samples, it can be easily incorporated into routine NIPT test and may enhance the current NIPT performance.
Highlights
Cell-free fetal DNA in maternal peripheral blood, discovered by Lo et al.[1], makes it possible to infer the fetal inheritance in a noninvasive way and led to the development of noninvasive prenatal applications, such as fetal sex determination for sex-linked disorders[2], detection of fetal chromosomal abnormalities[3,4], and detection of monogenic diseases[5,6,7,8]
From previous study25,we know that the fetal cell-free DNA (cfDNA) is nonuniformly distributed across the whole genome, so we divided the genome into 5 Mb region, resulting in regions across 22 autosomes (N-regions were excluded)
The methodology described in this study for the detection of fetal fraction relies on a simple and fundamental assumption that the fetal cfDNA has different alleles from the mother’s and this allele information is mixed in maternal plasma
Summary
Cell-free fetal DNA (cffDNA) in maternal peripheral blood, discovered by Lo et al.[1], makes it possible to infer the fetal inheritance in a noninvasive way and led to the development of noninvasive prenatal applications, such as fetal sex determination for sex-linked disorders[2], detection of fetal chromosomal abnormalities[3,4], and detection of monogenic diseases[5,6,7,8]. Several gender-independent methods rely upon the differential patterns between the maternal and fetal cfDNA, such as the distribution difference of fragment length[18], DNA methylation difference[19,20], and the fetal-specific alleles[5,21,22,23,24] These methods need additional laboratory test and are not costeffective for practical use. Given the fact that fetal cfDNA nonuniformly distributes across the genome relative to maternal cfDNA, the method SeqFF25 uses regional read counts to estimate FF. This method might not be robust for predicting low FF. The third one makes use of the heterozygosity of single nucleotide polymorphisms (SNPs), its accuracy might be limited for samples with sequencing depth
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