Non-invasive prenatal measurement of the fetal genome

Abstract

The vast majority of prenatal genetic testing requires invasive sampling. Since this poses a risk to the fetus, 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 noninvasively 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 noninvasively. We also applied the counting principle directly to each allele in the fetal exome by performing exome capture on maternal plasma DNA prior to shotgun sequencing. This approach enables noninvasive 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. Noninvasive determination of the fetal genome may ultimately facilitate the diagnosis of all inherited and de novo genetic disease.

Extracellular RNA profiles with human age

“…The discovery of circulating cell‐free DNA (extracellular DNA; exDNA) and RNA (extracellular RNA; exRNA) in human body fluids, including serum, has sparked great interest in whether these molecules are functional, have regulatory effects, or can be used as markers of disease. For example, exDNA found in maternal serum has led to significant advancements in prenatal testing and diagnosis (Chiu & Lo, 2013; Fan, Blumenfeld, Chitkara, Hudgins & Quake, 2008; Fan et al., 2012; Lo et al., 1997), and for prediction of heart transplant rejection in adults (De Vlaminck et al., 2014; Snyder, Khush, Valantine & Quake, 2011). …”

Secrets of life in a spoonful of blood

“…The field is racing ahead: a flurry of papers, from Lo 2,3 , Stephen Quake at Stanford University in California 4,5 and genome scientist Jay Shendure at the University of Washington in Seattle 6 have honed the resolution with which scientists can analyse a fetal genome from tiny bits of DNA floating in the mother's blood. They can now count the number of chromosomes in a fetus 2,4 , and are developing ever-more-accurate ways to sequence genomes.…”

Getting to know the fetal genome non-invasively: now a reality

“…In addition, these tests are not highly sensitive or specific to detect trisomies (Lo, 2012). An exciting recent study by HC Fan and her colleagues sought to tackle this problem and showed that it is possible to non-invasively determine the entire genome of the fetus prenatally (Fan et al, 2012).…”

“…However, the unique aspect of the study by Fan and colleagues is that, they demonstrated for the first time that acquiring the entire fetal genomic information is possible without having the paternal genetic map (Fan et al, 2012). This is extremely important in modern day world, where single parenthood and unknown paternity are common.…”

“…The fetal genome is a combination of four parental chromosomes, or haplotypes, that result from the process of random assortment as well as homologous recombination during the process of meiosis. Of the four fetal haplotypes, three haplotypes per genomic region are found in maternal serum during pregnancy (Fan et al, 2012). These include the maternal haplotypes that are transmitted to the fetus, the maternal haplotypes that are not transmitted to the fetus and the paternal haplotype that is transmitted (Fan et al, 2012).…”