Non-invasive whole genome sequencing of a human fetus

Analysis of cell-free fetal DNA in maternal plasma holds promise for the development of non-invasive prenatal genetic diagnostics. Previous studies have been restricted to detection of fetal trisomies (1, 2), specific paternally inherited mutations (3), or to genotyping common polymorphisms using material obtained invasively e.g. through chorionic villus sampling (4). Here, we combine genome sequencing of two parents, genome-wide maternal haplotyping (5), and deep sequencing of maternal plasma DNA to non-invasively determine the genome sequence of a human fetus at 18.5 weeks gestation. Inheritance was predicted at 2.8x106 parental heterozygous sites with 98.1% accuracy. Furthermore, 39 of 44 de novo point mutations in the fetal genome were detected, albeit with limited specificity. Subsampling these data and analyzing a second family trio by the same approach indicate that ~300 kilobase parental haplotype blocks combined with shallow sequencing of maternal plasma DNA is sufficient to substantially determine the inherited complement of a fetal genome. However, ultra-deep sequencing of maternal plasma DNA is necessary for the practical detection of fetal de novo mutations genome-wide. Although technical and analytical challenges remain, we anticipate that non-invasive analysis of inherited variation and de novo mutations in fetal genomes will facilitate prenatal diagnosis of both recessive and dominant Mendelian disorders.