Thus far, the focus of personalized medicine has been the prevention and treatment of conditions that affect adults. Although advances in genetic technology have been applied more frequently to prenatal diagnosis than to fetal treatment, genetic and genomic information is beginning to influence pregnancy management. Recent developments in sequencing the fetal genome combined with progress in understanding fetal physiology using gene expression arrays indicate that we could have the technical capabilities to apply an individualized medicine approach to the fetus. Here I review recent advances in prenatal genetic diagnostics, the challenges associated with these new technologies and how the information derived from them can be used to advance fetal care. Historically, the goal of prenatal diagnosis has been to provide an informed choice to prospective parents. We are now at a point where that goal can and should be expanded to incorporate genetic, genomic and transcriptomic data to develop new approaches to fetal treatment.
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Khoury, M.J. et al. The scientific foundation for personal genomics: recommendations from an NIH-CDC multidisciplinary workshop. Genet. Med. 11, 559–567 (2009).
Ferguson-Smith, M.A. & Bianchi, D.W. Prenatal diagnosis: past, present, and future. Prenat. Diagn. 30, 601–604 (2010).
Wolfberg, A.J. Genes on the web-direct-to-consumer marketing of genetic testing. N. Engl. J. Med. 355, 543–545 (2006).
Bianchi, D.W. At-home fetal DNA gender testing: caveat emptor. Obstet. Gynecol. 107, 216–218 (2006).
Hawkins, A.K. & Ho, A. Genetic counseling and the ethical issues around direct to consumer genetic testing. J. Genet. Counsel. 21, 367–373 (2012).
Miller, D.T. et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am. J. Hum. Genet. 86, 749–764 (2010).
Friedman, J.M. High-resolution array genomic hybridization in prenatal diagnosis. Prenat. Diagn. 29, 20–28 (2009).
Mailman, M.D. et al. The NCBI dbGAP database of genotypes and phenotypes. Nat. Genet. 39, 1181–1186 (2007).
Firth, H.V. et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am. J. Hum. Genet. 84, 524–533 (2009).
Anonymous. ACOG Committee Opinion No. 446: array comparative genomic hybridization in prenatal diagnosis. Obstet. Gynecol. 114, 1161–1163 (2009).
Schaeffer, A.J. et al. Comparative genomic hybridization-array analysis enhances the detection of aneuploidies and submicroscopic imbalances in spontaneous miscarriages. Am. J. Hum. Genet. 74, 1168–1174 (2004).
Raca, G. et al. Array-based comparative genomic hybridization (aCGH) in the genetic evaluation of stillbirth. Am. J. Med. Genet. A 149A, 2437–2443 (2009).
Harris, R.A. et al. Genome-wide array-based copy number profiling in human placentas from unexplained stillbirths. Prenat. Diagn. 31, 932–944 (2011).
Shaffer, L.G. et al. Comparison of microarray-based detection rates for cytogenetic abnormalities in prenatal and neonatal specimens. Prenat. Diagn. 28, 789–795 (2008).
Coppinger, J. et al. Whole-genome microarray analysis in prenatal specimens identifies clinically significant chromosome alterations without increase in results of unclear significance compared to targeted microarray. Prenat. Diagn. 29, 1156–1166 (2009).
Van den Veyver, I.B. et al. Clinical use of array comparative genomic hybridization (aCGH) for prenatal diagnosis in 300 cases. Prenat. Diagn. 29, 29–39 (2009).
Park, J.H. et al. Application of a target array comparative genomic hybridization to prenatal diagnosis. BMC Med. Genet. 11, 102 (2010).
Kleeman, L. et al. Use of array comparative genomic hybridization for prenatal diagnosis of fetuses with sonographic anomalies and normal metaphase karyotype. Prenat. Diagn. 29, 1213–1217 (2009).
Tyreman, M. et al. High resolution array analysis: diagnosing pregnancies with abnormal ultrasound findings. J. Med. Genet. 46, 531–541 (2009).
Faas, B.H. et al. Identification of clinically significant, submicroscopic chromosome alterations and UPD in fetuses with ultrasound anomalies using genome-wide 250k SNP array analysis. J. Med. Genet. 47, 586–594 (2010).
D'Amours, G. et al. Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype. Clin. Genet. 81, 128–141 (2012).
Maya, I. et al. Diagnostic utility of array-based comparative genomic hybridization (aCGH) in a prenatal setting. Prenat. Diagn. 30, 1131–1137 (2010).
Lo, Y.M. et al. Presence of fetal DNA in maternal plasma and serum. Lancet 350, 485–487 (1997).
Tjoa, M.L., Cindrova-Davies, T., Spasic-Boskovic, O., Bianchi, D.W. & Burton, G.J. Trophoblastic oxidative stress and the release of cell-free feto-placental DNA. Am. J. Pathol. 169, 400–404 (2006).
Alberry, M. et al. Free fetal DNA in maternal plasma in anembryonic pregnancies: confirmation that the origin is the trophoblast. Prenat. Diagn. 27, 415–418 (2007).
Bischoff, F.Z., Lewis, D.E. & Simpson, J.L. Cell-free fetal DNA in maternal blood: kinetics, source and structure. Hum. Reprod. Update 11, 59–67 (2005).
Masuzaki, H. et al. Detection of cell free placental DNA in maternal plasma: direct evidence from three cases of confined placental mosaicism. J. Med. Genet. 41, 289–292 (2004).
Sekizawa, A. et al. Evaluation of bidirectional transfer of plasma DNA through placenta. Hum. Genet. 113, 307–310 (2003).
Chim, S.S. et al. Detection of the placental epigenetic signature of the maspin gene in maternal plasma. Proc. Natl. Acad. Sci. USA 102, 14753–14758 (2005).
Chan, K.C. et al. Hypermethylated RASSF1A in maternal plasma: a universal fetal DNA marker that improves the reliability of noninvasive prenatal diagnosis. Clin. Chem. 52, 2211–2218 (2006).
Bennett, P.R. et al. Prenatal determination of fetal RhD type by DNA amplification. N. Engl. J. Med. 329, 607–610 (1993).
Lo, Y.M. et al. Prenatal diagnosis of fetal RhD status by molecular analysis of maternal plasma. N. Engl. J. Med. 339, 1734–1738 (1998).
Finning, K.M., Martin, P.G., Soothill, P.W. & Avent, N.D. Prediction of fetal D status from maternal plasma: introduction of a new noninvasive fetal RHD genotyping service. Transfusion 42, 1079–1085 (2002).
Bianchi, D.W., Avent, N.D., Costa, J.M. & van der Schoot, E.M. Noninvasive prenatal diagnosis of fetal Rhesus D: ready for prime(r) time. Obstet. Gynecol. 106, 841–844 (2005).
Scheffer, P.G., van der Schoot, C.E., Page-Christiaens, G.C. & de Haas, M. Noninvasive fetal blood group genotyping of rhesus D, c, E and of K in alloimmunised pregnant women: evaluation of a 7-year clinical experience. BJOG 118, 1340–1348 (2011).
Daniels, G., Finning, K. & Martin, P. Noninvasive fetal blood grouping: present and future. Clin. Lab. Med. 30, 431–442 (2010).
Clausen, F.B. et al. Report of the first nationally implemented clinical routine screening for fetal RHD in D- pregnant women to ascertain the requirements for antenatal D prophylaxis. Transfusion 52, 752–758 (2012).
Devaney, S.A., Palomaki, G.E., Scott, J.A. & Bianchi, D.W. Noninvasive fetal sex determination using cell-free fetal DNA. J. Am. Med. Assoc. 306, 627–636 (2011).
Hill, M. et al. Non-invasive prenatal determination of fetal sex: translating research into clinical practice. Clin. Genet. 80, 68–75 (2011).
ACOG Committee on Practice Bulletins. ACOG practice bulletin no. 77: screening for fetal chromosomal abnormalities. Obstet. Gynecol. 109, 217–227 (2007).
Bianchi, D.W. et al. Fetal gender and aneuploidy detection using fetal cells in maternal blood: analysis of NIFTY I data. National Institute of Child Health and Development Fetal Cell Isolation Study. Prenat. Diagn. 22, 609–615 (2002).
Bianchi, D.W. & Hanson, J. Sharpening the tools: a summary of a National Institutes of Health workshop on new technologies for detection of fetal cells in maternal blood for early prenatal diagnosis. J. Matern. Fetal Neonatal Med. 19, 199–207 (2006).
Lo, Y.M. Noninvasive prenatal detection of fetal chromosomal aneuploidies by maternal plasma nucleic acid analysis: a review of the current state of the art. BJOG 116, 152–157 (2009).
Lo, Y.M. et al. Plasma placental RNA allelic ratio permits noninvasive prenatal chromosomal aneuploidy detection. Nat. Med. 13, 218–223 (2007).
Tsui, N.B. et al. Synergy of total PLAC4 RNA concentration and measurement of the RNA single-nucleotide polymorphism allelic ratio for the noninvasive prenatal detection of trisomy 21. Clin. Chem. 56, 73–81 (2010).
Lo, Y.M. et al. Digital PCR for the molecular detection of fetal chromosomal aneuploidy. Proc. Natl. Acad. Sci. USA 104, 13116–13121 (2007).
Fan, H.C. & Quake, S.R. Detection of aneuploidy with digital polymerase chain reaction. Anal. Chem. 79, 7576–7579 (2007).
Fan, H.C., Blumenfeld, Y.J., Chitkara, U., Hudgins, L. & Quake, S.R. Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood. Proc. Natl. Acad. Sci. USA 105, 16266–16271 (2008).
Chiu, R.W. et al. Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc. Natl. Acad. Sci. USA 105, 20458–20463 (2008).
Chiu, R.W. et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. Br. Med. J. 342, c7401 (2011).
Ehrich, M. et al. Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting. Am. J. Obstet. Gynecol. 204, 205.e1–11 (2011).
Sehnert, A.J. et al. Optimal detection of fetal chromosomal abnormalities by massively parallel sequencing of cell-free fetal DNA from maternal blood. Clin. Chem. 57, 1042–1049 (2011).
Chen, E.Z. et al. Noninvasive prenatal diagnosis of fetal trisomy 18 and trisomy 13 by maternal plasma DNA sequencing. PLoS ONE 6, e21791 (2011).
Palomaki, G.E. et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet. Med. 13, 913–920 (2011).
Palomaki, G.E. et al. DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study. Genet. Med. 14, 296–305 (2012).
Bianchi, D.W. et al. Genome-wide fetal aneuploidy detection by maternal plasma DNA sequencing. Obstet. Gynecol. 119, 890–901 (2012).
Sparks, A.B. et al. Selective analysis of cell-free DNA in maternal blood for evaluation of fetal trisomy. Prenat. Diagn. 32, 3–9 (2012).
Ashoor, G., Syngelaki, A., Wagner, M., Birdir, C. & Nicolaides, K.H. Chromosome-selective sequencing of maternal plasma cell-free DNA for first-trimester detection of trisomy 21 and trisomy 18. Am. J. Obstet. Gynecol. 206, 322.e1–5 (2012).
Sparks, A.B., Struble, C.A., Wang, E.T., Song, K. & Oliphant, A. Non-invasive prenatal detection and selective analysis of cell-free DNA obtained from maternal blood: evaluation for trisomy 21 and trisomy 18. Am. J. Obstet. Gynecol. 206, 319.e1–9 (2012).
Lun, F.M. et al. Noninvasive prenatal diagnosis of a case of Down syndrome due to Robertsonian translocation by massively parallel sequencing of maternal plasma DNA. Clin. Chem. 57, 917–919 (2011).
Benn, P. et al. Prenatal detection of Down syndrome using massively parallel sequencing (MPS): a rapid response statement from a committee on behalf of the Board of the International Society for Prenatal Diagnosis, 24 October 2011. Prenat. Diagn. 32, 1–2 (2012).
Lui, Y.Y. et al. Predominant hematopoietic origin of cell-free DNA in plasma and serum after sex-mismatched bone marrow transplantation. Clin. Chem. 48, 421–427 (2002).
Lo, Y.M. et al. Maternal plasma DNA sequencing reveals the genome-wide genetic and mutational profile of the fetus. Sci. Transl. Med. 2, 61ra91 (2010).
Fan, H.C. et al. Analysis of the size distributions of fetal and maternal cell-free DNA by paired-end sequencing. Clin. Chem. 56, 1279–1286 (2010).
Chan, K.C. et al. Size distributions of maternal and fetal DNA in maternal plasma. Clin. Chem. 50, 88–92 (2004).
Lun, F.M. et al. Microfluidics digital PCR reveals a higher than expected fraction of fetal DNA in maternal plasma. Clin. Chem. 54, 1664–1672 (2008).
Peters, D. et al. Noninvasive prenatal diagnosis of a fetal microdeletion syndrome. N. Engl. J. Med. 365, 1847–1848 (2011).
Lun, F.M. et al. Noninvasive prenatal diagnosis of monogenic diseases by digital size selection and relative mutation dosage on DNA in maternal plasma. Proc. Natl. Acad. Sci. USA 105, 19920–19925 (2008).
Barrett, A.N., McDonnell, T.C., Chan, K.C. & Chitty, L.S. Digital PCR analysis of maternal plasma for noninvasive detection of sickle cell anemia. Clin. Chem. (2012).
Tsui, N.B. et al. Noninvasive prenatal diagnosis of hemophilia by microfluidics digital PCR analysis of maternal plasma DNA. Blood 117, 3684–3691 (2011).
Lo, Y.M. et al. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am. J. Hum. Genet. 62, 768–775 (1998).
Chiu, R.W. et al. Time profile of appearance and disappearance of circulating placenta-derived mRNA in maternal plasma. Clin. Chem. 52, 313–316 (2006).
Poon, L.L., Leung, T.N., Lau, T.K. & Lo, Y.M. Presence of fetal RNA in maternal plasma. Clin. Chem. 46, 1832–1834 (2000).
Tsui, N.B., Ng, E.K. & Lo, Y.M. Stability of endogenous and added RNA in blood specimens, serum, and plasma. Clin. Chem. 48, 1647–1653 (2002).
Ng, E.K. et al. mRNA of placental origin is readily detectable in maternal plasma. Proc. Natl. Acad. Sci. USA 100, 4748–4753 (2003).
Heung, M.M. et al. Placenta-derived fetal specific mRNA is more readily detectable in maternal plasma than in whole blood. PLoS ONE 4, e5858 (2009).
Maron, J.L. et al. Gene expression analysis in pregnant women and their infants identifies unique fetal biomarkers that circulate in maternal blood. J. Clin. Invest. 117, 3007–3019 (2007).
Bianchi, D.W., Maron, J.L. & Johnson, K.L. Insights into fetal and neonatal development through analysis of cell-free RNA in body fluids. Early Hum. Dev. 86, 747–752 (2010).
Luo, S.S. et al. Human villous trophoblasts express and secrete placenta-specific microRNAs into maternal circulation via exosomes. Biol. Reprod. 81, 717–729 (2009).
Pineles, B.L. et al. Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia. Am. J. Obstet. Gynecol. 196, 261.e1–6 (2007).
Mouillet, J.F. et al. The levels of hypoxia-regulated microRNAs in plasma of pregnant women with fetal growth restriction. Placenta 31, 781–784 (2010).
Chim, S.S. et al. Detection and characterization of placental microRNAs in maternal plasma. Clin. Chem. 54, 482–490 (2008).
Miura, K. et al. Identification of pregnancy-associated microRNAs in maternal plasma. Clin. Chem. 56, 1767–1771 (2010).
Kotlabova, K., Doucha, J. & Hromadnikova, I. Placental-specific microRNA in maternal circulation-identification of appropriate pregnancy-associated microRNAs with diagnostic potential. J. Reprod. Immunol. 89, 185–191 (2011).
Larrabee, P.B. et al. Global gene expression analysis of the living human fetus using cell-free messenger RNA in amniotic fluid. J. Am. Med. Assoc. 293, 836–842 (2005).
Slonim, D.K. et al. Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses. Proc. Natl. Acad. Sci. USA 106, 9425–9429 (2009).
Koide, K. et al. Transcriptomic analysis of cell-free fetal RNA suggests a specific molecular phenotype in trisomy 18. Hum. Genet. 129, 295–305 (2011).
Zana, M., Janka, Z. & Kalman, J. Oxidative stress: a bridge between Down's syndrome and Alzheimer's disease. Neurobiol. Aging 28, 648–676 (2007).
Lamb, J. et al. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313, 1929–1935 (2006).
FitzPatrick, D.R. et al. Transcriptome analysis of human autosomal trisomy. Hum. Mol. Genet. 11, 3249–3256 (2002).
Chung, I.H. et al. Gene expression analysis of cultured amniotic fluid cell with Down syndrome by DNA microarray. J. Korean Med. Sci. 20, 82–87 (2005).
Rozovski, U. et al. Genome-wide expression analysis of cultured trophoblast with trisomy 21 karyotype. Hum. Reprod. 22, 2538–2545 (2007).
Hui, L. et al. The amniotic fluid transcriptome: a source of novel information about human fetal development. Obstet. Gynecol. 119, 111–118 (2012).
Tsui, N.B. et al. Systematic micro-array based identification of placental mRNA in maternal plasma: towards non-invasive prenatal gene expression profiling. J. Med. Genet. 41, 461–467 (2004).
Purwosunu, Y. et al. Cell-free mRNA concentrations of CRH, PLAC1, and selectin-P are increased in the plasma of pregnant women with preeclampsia. Prenat. Diagn. 27, 772–777 (2007).
Okazaki, S. et al. Placenta-derived, cellular messenger RNA expression in the maternal blood of preeclamptic women. Obstet. Gynecol. 110, 1130–1136 (2007).
Miura, K. et al. The possibility of microarray-based analysis using cell-free placental mRNA in maternal plasma. Prenat. Diagn. 30, 849–861 (2010).
Miura, K. et al. Increased levels of cell-free placenta mRNA in a subgroup of placenta previa that needs hysterectomy. Prenat. Diagn. 28, 805–809 (2008).
Ng, E.K. et al. The concentration of circulating corticotrophin-releasing hormone mRNA in maternal plasma is increased in preeclampsia. Clin. Chem. 49, 727–731 (2003).
Løset, M. et al. A transcriptional profile of the decidua in preeclampsia. Am. J. Obstet. Gynecol. 204, 84.e1–27 (2011).
Sitras, V., Paulssen, R., Leirvik, J., Vartun, A. & Acharya, G. Placental gene expression profile in intrauterine growth restriction due to placental insufficiency. Reprod. Sci. 16, 701–711 (2009).
Madsen-Bouterse, S.A. et al. The transcriptome of the fetal inflammatory response syndrome. Am. J. Reprod. Immunol. 63, 73–92 (2010).
Gracie, S.K. et al. All Our Babies Cohort Study: recruitment of a cohort to predict women at risk of preterm birth through the examination of gene expression profiles and the environment. BMC Pregnancy Childbirth 10, 87 (2010).
Guttmacher, A.E. et al. Educating health-care professionals about genetics and genomics. Nat. Rev. Genet. 8, 151–157 (2007).
Wapner, R. A multicenter, prospective, masked comparison of chromosomal microarray with standard karyotyping for routine and high risk prenatal diagnosis. Am. J. Obstet. Gynecol. 206, S2 (2012).
Susman, M.R. et al. Using population-based data to predict the impact of introducing noninvasive prenatal diagnosis for Down syndrome. Genet. Med. 12, 298–303 (2010).
Benn, P.A. & Chapman, A.R. Practical and ethical considerations of noninvasive prenatal diagnosis. J. Am. Med. Assoc. 301, 2154–2156 (2009).
Hill, M. et al. Incremental cost of non-invasive prenatal diagnosis versus invasive prenatal diagnosis of fetal sex in England. Prenat. Diagn. 31, 267–273 (2011).
Liao, G.J. et al. Targeted massively parallel sequencing of maternal plasma DNA permits efficient and unbiased detection of fetal alleles. Clin. Chem. 57, 92–101 (2011).
Papageorgiou, E.A. et al. Fetal-specific DNA methylation ratio permits noninvasive prenatal diagnosis of trisomy 21. Nat. Med. 17, 510–513 (2011).
Ghanta, S. et al. Non-invasive prenatal detection of trisomy 21 using tandem single nucleotide polymorphisms. PLoS ONE 5, e13184 (2010).
Benn, P.A. & Chapman, A.R. Ethical challenges in providing noninvasive prenatal diagnosis. Curr. Opin. Obstet. Gynecol. 22, 128–134 (2010).
Beaudet, A.L. Ethical issues raised by common copy number variants and single nucleotide polymorphisms of certain and uncertain significance in general medical practice. Genome Med. 2, 42 (2010).
Greely, H.T. Get ready for the flood of fetal gene screening. Nature 469, 289–291 (2011).
Deans, Z. & Newson, A.J. Should non-invasiveness change informed consent procedures for prenatal diagnosis? Health Care Anal. 19, 122–132 (2011).
Hall, A., Bostanci, A. & Wright, C.F. Non-invasive prenatal diagnosis using cell-free fetal DNA technology: applications and implications. Public Health Genomics 13, 246–255 (2010).
Massingham, L.J. et al. Proof of concept study to assess fetal gene expression in amniotic fluid by nanoarray PCR. J. Mol. Diagn. 13, 565–570 (2011).
The author would like to thank D. Walt, E. Norwitz, J. Maron and L. Hui for their critical reading of the manuscript and their suggestions. In addition, she is grateful for the administrative support provided by R. Forman. The author's time and effort in writing this manuscript was partially supported by the US National Institutes of Health grant HD42053-09.
D.W.B. is Chair of the Clinical Advisory Board of Verinata Health, Inc. and receives honoraria and equity options in the company for this role.
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Bianchi, D. From prenatal genomic diagnosis to fetal personalized medicine: progress and challenges. Nat Med 18, 1041–1051 (2012). https://doi.org/10.1038/nm.2829
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