Analysis of cell-free fetal DNA in maternal plasma holds promise for the development of noninvasive prenatal genetic diagnostics. Previous studies have been restricted to detection of fetal trisomies, to specific paternally inherited mutations, or to genotyping common polymorphisms using material obtained invasively, for example, through chorionic villus sampling. Here, we combine genome sequencing of two parents, genome-wide maternal haplotyping, and deep sequencing of maternal plasma DNA to noninvasively determine the genome sequence of a human fetus at 18.5 weeks of gestation. Inheritance was predicted at 2.8 × 106 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 parental haplotype blocks of ~300 kilo–base pairs combined with shallow sequencing of maternal plasma DNA is sufficient to substantially determine the inherited complement of a fetal genome. However, ultradeep 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 noninvasive analysis of inherited variation and de novo mutations in fetal genomes will facilitate prenatal diagnosis of both recessive and dominant Mendelian disorders.
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The ability to noninvasively sequence a fetal genome to high accuracy and completeness will undoubtedly have profound implications for the future of prenatal genetic diagnostics. Although individually rare, when considered collectively, the ~3500 Mendelian disorders with a known molecular basis (19) contribute substantially to morbidity and mortality (20). Currently, routine obstetric practice includes offering a spectrum of screening and diagnostic options to all women. Prenatal screening options have imperfect sensitivity and focus mainly on a small number of specific disorders, including trisomies, major congenital anomalies, and specific Mendelian disorders. Diagnostic tests, generally performed through invasive procedures, such as chorionic villus sampling and amniocentesis, also focus on specific disorders and confer risk of pregnancy loss that may inversely correlate with access to high-quality care. Noninvasive, comprehensive diagnosis of Mendelian disorders early in pregnancy would provide much more information to expectant parents, with the greater accessibility inherent to a noninvasive test and without tangible risk of pregnancy loss. The less tangible implication of incorporating this level of information into prenatal decision-making raises many ethical questions that must be considered carefully within the scientific community and on a societal level. A final point is that as in other areas of clinical genetics, our capacity to generate data is outstripping our ability to interpret it in ways that are useful to physicians and patients. That is, although the noninvasive prediction of a fetal genome may be technically feasible, its interpretation—even for known Mendelian disorders—will remain a major challenge.