Journal Article

Non-invasive prenatal measurement of the fetal genome

Fan, H. Christina, Wang, Jianbin, Blumenfeld, Yair J., El-Sayed, Yasser Y., Gu, Wei, Quake, Stephen R.

2012

Overview

The vast majority of prenatal genetic testing requires invasive sampling. However, this poses a risk to the fetus, so one must make a decision that weighs the desire for genetic information against the risk of an adverse outcome due to hazards of the testing process. These issues are not required to be coupled, and it would be desirable to discover genetic information about the fetus without incurring a health risk. Here we demonstrate that it is possible to non-invasively sequence the entire prenatal genome. Our results show that molecular counting of parental haplotypes in maternal plasma by shotgun sequencing of maternal plasma DNA allows the inherited fetal genome to be deciphered non-invasively. We also applied the counting principle directly to each allele in the fetal exome by performing exome capture on maternal plasma DNA before shotgun sequencing. This approach enables non-invasive exome screening of clinically relevant and deleterious alleles that were paternally inherited or had arisen as de novo germline mutations, and complements the haplotype counting approach to provide a comprehensive view of the fetal genome. Non-invasive determination of the fetal genome may ultimately facilitate the diagnosis of all inherited and de novo genetic disease. Prenatal testing usually requires invasive sampling; here molecular counting of parental haplotypes in the maternal plasma allows the fetal genome to be deciphered and molecular counting of individual alleles enables the fetal exome to be captured. Fetal genome screened non-invasively Prenatal genetic testing usually requires invasive sampling, with associated risks to the health of the fetus and mother. Here, Stephen Quake and colleagues describe how molecular counting can be used to reconstruct the fetal genome non-invasively from maternal blood. They use shotgun sequencing to determine which of the two haplotypes within each parent is over-represented in maternal plasma DNA and has therefore been inherited by the fetus. The fetal exome can then be screened for clinically relevant alleles that were paternally inherited or had arose as de novo germline mutations.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/212 / 631/61/514/1948 / 692/700/139 / Biological and medical sciences / Chromosomes / Chromosomes, Human - genetics / Deoxyribonucleic acid / DNA / DNA - analysis / DNA - blood / Exome - genetics / Female / Fetus / Fetuses / General aspects. Genetic counseling / Genetic aspects / Genetic screening / Genetic testing / Genome, Human / Genomes / Haplotypes / Health aspects / Health risks / Humanities and Social Sciences / Humans / Male / Measurement / Medical genetics / Medical sciences / Methods / multidisciplinary / Plasma / Pregnancy / Prenatal diagnosis / Prenatal Diagnosis - methods / Science / Sensitivity and Specificity