Haplotype-assisted accurate noninvasive fetal whole genome recovery through maternal plasma sequencing
Genome Medicine 2013, 5:18 doi:10.1186/gm422Published: 27 February 2013
The applications of massively parallel sequencing technology to fetal cell-free DNA (cff-DNA) have brought new insight to noninvasive prenatal diagnosis. However, most previous research based on maternal plasma sequencing has been restricted to fetal aneuploidies. To detect specific parentally inherited mutations, invasive approaches to obtain fetal DNA are the current standard in the clinic because of the experimental complexity and resource consumption of previously reported noninvasive approaches.
Here, we present a simple and effective noninvasive method for accurate fetal genome recovery-assisted with parental haplotypes. The parental haplotype were firstly inferred using a combination strategy of trio and unrelated individuals. Assisted with the parental haplotype, we then employed a hidden Markov model to noninvasively recover the fetal genome through maternal plasma sequencing.
Using ~44X sequence depth against a ~5.69% cff-DNA concentration, we noninvasively inferred fetal genotype and haplotype under different situations of parental heterozygosity. Our data show that 98.57%, 95.37% and 98.45% of paternal autosome alleles, maternal autosome alleles and maternal chromosome X in the fetal haplotypes, respectively, were recovered accurately. Additionally, we obtained efficient coverage or strong linkage of 96.65% of reported Mendelian-disorder genes and 98.90% of complex disease-associated markers.
Our method provides a useful strategy for noninvasive whole fetal genome recovery. See related Commentary article: http://www.biomedcentral.com/1741-7015/11/56