Research ArticlePrenatal Diagnosis

Maternal Plasma DNA Sequencing Reveals the Genome-Wide Genetic and Mutational Profile of the Fetus

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Science Translational Medicine  08 Dec 2010:
Vol. 2, Issue 61, pp. 61ra91
DOI: 10.1126/scitranslmed.3001720

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Maternal Plasma Yields Fetal Secrets

Plasma from a pregnant woman is known to contain small amounts not only of maternal DNA but also of fetal DNA. Although only 10% of cell-free DNA in maternal plasma is of fetal origin, next-generation sequencing technology should enable sequencing of fetal DNA fragments that could then be assembled into a full genetic map (with the parental genomes as guides). The fetal genome then could be scanned for mutations prenatally and noninvasively. In a proof-of-concept study in a family where both parents carry mutations for the blood disease β-thalassemia, Lo and colleagues now use this approach to identify whether the fetus carries no, one, or even two β-thalassemia mutations.

Using massively parallel sequencing, these investigators sequenced DNA in the plasma of the pregnant mother to 65-fold genome coverage. They demonstrated that the full maternal and fetal genomes were present in maternal plasma at constant proportions and that maternal and fetal DNA showed distinctive fragmentation patterns. Next, the authors assembled a complete fetal genomic map, using the paternal genotype and maternal haplotype (deduced from a chorionic villus sample) as guides. They then scanned the fetal genome to see whether the fetus had inherited β-thalassemia.

β-Thalassemia is an autosomal recessive disease characterized by severe anemia and is caused by mutations in the HBB gene encoding the β subunit of hemoglobin. To inherit the disease, the fetus must carry mutations from both parents. The pregnant mother carried one HBB gene mutation, and the father carried a different mutation. The authors conducted genome-wide genotyping of maternal and paternal DNA derived from blood cells for ~900,000 single-nucleotide polymorphisms (SNPs) and divided the SNPs into five categories. From the maternal plasma DNA sequencing data, they searched for and found the paternal mutation inherited by the fetus. They then used relative haplotype dosage (RHDO) analysis to see whether the fetus had inherited the genomic region that contained the maternal mutation. They found that the fetus had not inherited the maternal mutation and thus was a heterozygous carrier for β-thalassemia. Although still at the proof-of-concept stage, this study shows that sequencing of maternal plasma DNA provides a way for noninvasive prenatal genome-wide scanning for genetic disorders.


  • Citation: Y. M. D. Lo, K. C. A. Chan, H. Sun, E. Z. Chen, P. Jiang, F. M. F. Lun, Y. W. Zheng, T. Y. Leung, T. K. Lau, C. R. Cantor, R. W. K. Chiu, Maternal Plasma DNA Sequencing Reveals the Genome-Wide Genetic and Mutational Profile of the Fetus. Sci. Transl. Med. 2, 61ra91 (2010).

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