Abstract
Whole exome sequencing (WES) is increasingly being used in the prenatal setting. The emerging data support the clinical utility of prenatal WES based on its diagnostic yield, which can be as high as 80% for certain ultrasound findings. However, detailed practice and laboratory guidelines, addressing the indications for prenatal WES and the surrounding technical, interpretation, ethical, and counseling issues, are still lacking. Herein, we review the literature and summarize the most recent findings and applications of prenatal WES. This review offers specialists and clinical genetic laboratorians a body of evidence and expert opinions that can serve as a resource to assist in their practice. Finally, we highlight the emerging technologies that promise a future of prenatal WES without the risks associated with invasive testing.
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References
Aarabi M, Sniezek O, Jiang H, Saller DN, Bellissimo D, Yatsenko SA, Rajkovic A (2018) Importance of complete phenotyping in prenatal whole exome sequencing. Hum Genet 137:175–181. https://doi.org/10.1007/s00439-017-1860-1
Abou Tayoun AN, Spinner NB, Rehm HL, Green RC, Bianchi DW (2018) Prenatal DNA sequencing: clinical, counseling, and diagnostic laboratory considerations. Prenat Diagn 38:26–32. https://doi.org/10.1002/pd.5038
ACMG Board of Directors (2012) Points to consider in the clinical application of genomic sequencing. Genet Med 14:759–761. https://doi.org/10.1038/gim.2012.74
Adinolfi M, El-Hashemite N, Sherlock J, Ward RH, Petrou M, Rodeck C (1997) Prenatal detection of Hb mutations using transcervical cells. Prenat Diagn 17:539–543
Alamillo CL et al (2015) Exome sequencing positively identified relevant alterations in more than half of cases with an indication of prenatal ultrasound anomalies. Prenat Diagn 35:1073–1078. https://doi.org/10.1002/pd.4648
Amr SS et al (2018) Allele-specific droplet digital PCR combined with a next-generation sequencing-based algorithm for diagnostic copy number analysis in genes with high homology: proof of concept using Stereocilin. Clin Chem 64:705–714. https://doi.org/10.1373/clinchem.2017.280685
Austin-Tse CA, Mandelker DL, Oza AM, Mason-Suares H, Rehm HL, Amr SS (2018) Analysis of intragenic USH2A copy number variation unveils broad spectrum of unique and recurrent variants. Eur J Med Genet 61:621–626. https://doi.org/10.1016/j.ejmg.2018.04.006
Avent ND (2008) RHD genotyping from maternal plasma: guidelines and technical challenges. Methods Mol Biol 444:185–201. https://doi.org/10.1007/978-1-59745-066-9_14
Baylor Genetics (2018) Performance of the newly developed non-invasive prenatal multi-gene sequencing screen. White Paper. https://www.baylorgenetics.com/preseek/. Accessed 1 June 2018
Beaudet AL (2016) Using fetal cells for prenatal diagnosis: history and recent progress. Am J Med Genet C Semin Med Genet 172:123–127. https://doi.org/10.1002/ajmg.c.31487
Bernhardt BA, Soucier D, Hanson K, Savage MS, Jackson L, Wapner RJ (2013) Women’s experiences receiving abnormal prenatal chromosomal microarray testing results. Genet Med 15:139–145. https://doi.org/10.1038/gim.2012.113
Best S, Wou K, Vora N, Van der Veyver IB, Wapner R, Chitty LS (2018) Promises, pitfalls and practicalities of prenatal whole exome sequencing. Prenat Diagn 38:10–19. https://doi.org/10.1002/pd.5102
Bischoff FZ, Simpson JL (2006) Endocervical fetal trophoblast for prenatal genetic diagnosis. Curr Opin Obstet Gynecol 18:216–220. https://doi.org/10.1097/01.gco.0000192985.22718.17
Bischoff FZ et al (2003) Intact fetal cells in maternal plasma: are they really there? Lancet (London, England) 361:139–140. https://doi.org/10.1016/S0140-6736(03)12191-5
Bolnick JM et al (2014) Trophoblast retrieval and isolation from the cervix (TRIC) for noninvasive prenatal screening at 5–20 weeks of gestation. Fertil Steril 102:135–142. https://doi.org/10.1016/j.fertnstert.2014.04.008
Bolnick AD et al (2016a) Trophoblast Retrieval and Isolation from the Cervix for noninvasive, first trimester, fetal gender determination in a carrier of congenital adrenal hyperplasia. Reprod Sci (Thousand Oaks, Calif) 23:717–722. https://doi.org/10.1177/1933719116632922
Bolnick JM et al (2016b) Altered biomarkers in trophoblast cells obtained noninvasively prior to clinical manifestation of perinatal disease. Sci Rep 6:32382. https://doi.org/10.1038/srep32382
Boone PM et al (2013) Deletions of recessive disease genes: CNV contribution to carrier states and disease-causing alleles. Genome Res 23:1383–1394. https://doi.org/10.1101/gr.156075.113
Botkin JR et al (2015) Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet 97:6–21. https://doi.org/10.1016/j.ajhg.2015.05.022
Brady P et al (2016) Clinical implementation of NIPT—technical and biological challenges. Clin Genet 89:523–530. https://doi.org/10.1111/cge.12598
Carss KJ, Hillman SC, Parthiban V, McMullan DJ, Maher ER, Kilby MD, Hurles ME (2014) Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound. Hum Mol Genet 23:3269–3277. https://doi.org/10.1093/hmg/ddu038
Chandler N et al (2018) Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management. Genet Med. https://doi.org/10.1038/gim.2018.30
Chitty LS (2018) Advances in the prenatal diagnosis of monogenic disorders. Prenat Diagn 38:3–5. https://doi.org/10.1002/pd.5208
Chitty LS, Mason S, Barrett AN, McKay F, Lench N, Daley R, Jenkins LA (2015) Non-invasive prenatal diagnosis of achondroplasia and thanatophoric dysplasia: next-generation sequencing allows for a safer, more accurate, and comprehensive approach. Prenat Diagn 35:656–662. https://doi.org/10.1002/pd.4583
Chiu EKL, Hui WWI, Chiu RWK (2018) cfDNA screening and diagnosis of monogenic disorders—where are we heading? Prenat Diagn 38:52–58. https://doi.org/10.1002/pd.5207
Cirigliano V, Sherlock J, Petrou M, Ward RH, Rodeck C, Adinolfi M (1999) Transcervical cells and the prenatal diagnosis of haemoglobin (Hb) mutations. Clin Genet 56:357–361
Clark MJ et al (2011) Performance comparison of exome DNA sequencing technologies. Nat Biotechnol 29:908–914. https://doi.org/10.1038/nbt.1975
Clausen FB (2014) Integration of noninvasive prenatal prediction of fetal blood group into clinical prenatal care. Prenat Diagn 34:409–415. https://doi.org/10.1002/pd.4326
Committee on Practice Bulletins-Obstetrics CoG, the Society for Maternal-Fetal M (2016) Practice Bulletin No. 163: screening for fetal aneuploidy. Obstet Gynecol 127:e123–e137. https://doi.org/10.1097/aog.0000000000001406
Daley R, Hill M, Chitty LS (2014) Non-invasive prenatal diagnosis: progress and potential. Arch Dis Child Fetal Neonatal Ed 99:F426–F430. https://doi.org/10.1136/archdischild-2013-304828
Daoud H et al (2016) Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit. CMAJ 188:E254–E260. https://doi.org/10.1503/cmaj.150823
Drury S, Williams H, Trump N, Boustred C, Lench N, Scott RH, Chitty LS (2015) Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities. Prenat Diagn 35:1010–1017. https://doi.org/10.1002/pd.4675
Filges I, Friedman JM (2015) Exome sequencing for gene discovery in lethal fetal disorders—harnessing the value of extreme phenotypes. Prenat Diagn 35:1005–1009. https://doi.org/10.1002/pd.4464
Fritz R et al (2015a) Noninvasive detection of trophoblast protein signatures linked to early pregnancy loss using trophoblast retrieval and isolation from the cervix (TRIC). Fertil Steril 104:339–346. https://doi.org/10.1016/j.fertnstert.2015.05.010
Fritz R et al (2015b) Trophoblast retrieval and isolation from the cervix (TRIC) is unaffected by early gestational age or maternal obesity. Prenat Diagn 35:1218–1222. https://doi.org/10.1002/pd.4681
Fu F et al (2018) Whole exome sequencing as a diagnostic adjunct to clinical testing in fetuses with structural abnormalities. Ultrasound Obstet Gynecol 51:493–502. https://doi.org/10.1002/uog.18915
Green RC et al (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15:565–574. https://doi.org/10.1038/gim.2013.73
Imudia AN, Suzuki Y, Kilburn BA, Yelian FD, Diamond MP, Romero R, Armant DR (2009) Retrieval of trophoblast cells from the cervical canal for prediction of abnormal pregnancy: a pilot study. Hum Reprod 24:2086–2092. https://doi.org/10.1093/humrep/dep206
International Society for Prenatal Diagnosis, Society for M, Fetal M, Perinatal Quality F (2018) Joint Position Statement from the International Society for Prenatal Diagnosis (ISPD), the Society for Maternal Fetal Medicine (SMFM), and the Perinatal Quality Foundation (PQF) on the use of genome-wide sequencing for fetal diagnosis. Prenat Diagn 38:6–9. https://doi.org/10.1002/pd.5195
Jain CV et al (2016) Fetal genome profiling at 5 weeks of gestation after noninvasive isolation of trophoblast cells from the endocervical canal. Sci Transl Med 8:363re4. https://doi.org/10.1126/scitranslmed.aah4661
Kalia SS et al (2017) Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med 19:249–255. https://doi.org/10.1038/gim.2016.190
Kalynchuk EJ, Althouse A, Parker LS, Saller DN Jr, Rajkovic A (2015) Prenatal whole-exome sequencing: parental attitudes. Prenat Diagn 35:1030–1036. https://doi.org/10.1002/pd.4635
Kobayashi Y, Yang S, Nykamp K, Garcia J, Lincoln SE, Topper SE (2017) Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation. Genome Med 9:13. https://doi.org/10.1186/s13073-017-0403-7
Korfhage C, Fisch E, Fricke E, Baedker S, Loeffert D (2013) Whole-genome amplification of single-cell genomes for next-generation sequencing. Curr Protoc Mol Biol 104:7–14. https://doi.org/10.1002/0471142727.mb0714s104
Korpi-Steiner N, Chiu RWK, Chandrasekharan S, Chitty LS, Evans MI, Jackson JA, Palomaki GE (2017) Emerging considerations for noninvasive prenatal testing. Clin Chem 63:946–953. https://doi.org/10.1373/clinchem.2016.266544
LaDuca H et al (2017) Exome sequencing covers > 98% of mutations identified on targeted next generation sequencing panels. PLoS One 12:e0170843. https://doi.org/10.1371/journal.pone.0170843
Lander ES et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921. https://doi.org/10.1038/35057062
Ledbetter DH et al (1992) Cytogenetic results from the US collaborative study on CVS. Prenat Diagn 12:317–345
Lee KA et al (2009) PTPN11 analysis for the prenatal diagnosis of Noonan syndrome in fetuses with abnormal ultrasound findings. Clin Genet 75:190–194. https://doi.org/10.1111/j.1399-0004.2008.01085.x
Lei TY et al (2017) Whole-exome sequencing for prenatal diagnosis of fetuses with congenital anomalies of the kidney and urinary tract. Nephrol Dial Transplant 32:1665–1675. https://doi.org/10.1093/ndt/gfx031
Lench N et al (2013) The clinical implementation of non-invasive prenatal diagnosis for single-gene disorders: challenges and progress made. Prenat Diagn 33:555–562. https://doi.org/10.1002/pd.4124
Li N et al (2015) The performance of whole genome amplification methods and next-generation sequencing for pre-implantation genetic diagnosis of chromosomal abnormalities. J Genet Genom 42:151–159. https://doi.org/10.1016/j.jgg.2015.03.001
Lincoln SE et al (2019) A rigorous interlaboratory examination of the need to confirm next-generation sequencing-detected variants with an orthogonal method in clinical genetic testing. J Mol Diagn 21:318–329. https://doi.org/10.1016/j.jmoldx.2018.10.009
Loke YW et al (1997) Evaluation of trophoblast HLA-G antigen with a specific monoclonal antibody. Tissue Antigens 50:135–146
Mandelker D et al (2014) Comprehensive diagnostic testing for stereocilin: an approach for analyzing medically important genes with high homology. J Mol Diagn 16:639–647. https://doi.org/10.1016/j.jmoldx.2014.06.003
Margulies M et al (2005) Genome sequencing in microfabricated high-density picolitre reactors. Nature 437:376–380. https://doi.org/10.1038/nature03959
Mason-Suares H, Landry L, Lebo MS (2016) Detecting copy number variants via next generation sequencing technologies. Curr Genet Med Rep 3:74–85
McMaster M, Zhou Y, Shorter S, Kapasi K, Geraghty D, Lim KH, Fisher S (1998) HLA-G isoforms produced by placental cytotrophoblasts and found in amniotic fluid are due to unusual glycosylation. J Immunol 160:5922–5928
Meng L et al (2017) Use of exome sequencing for infants in intensive care units: ascertainment of severe single-gene disorders and effect on medical management. JAMA Pediatr 171:e173438. https://doi.org/10.1001/jamapediatrics.2017.3438
Mitchell C et al (2017) Exploring the potential duty of care in clinical genomics under UK law. Med Law Int 17:158–182. https://doi.org/10.1177/0968533217721966
Moser G, Drewlo S, Huppertz B, Armant DR (2018) Trophoblast retrieval and isolation from the cervix: origins of cervical trophoblasts and their potential value for risk assessment of ongoing pregnancies. Hum Reprod Update. https://doi.org/10.1093/humupd/dmy008
Nabieva E et al (2019) Accurate fetal variant calling in the presence of maternal cell contamination. bioRxiv. https://doi.org/10.1101/552414
Nagan N, Faulkner NE, Curtis C, Schrijver I (2011) Laboratory guidelines for detection, interpretation, and reporting of maternal cell contamination in prenatal analyses a report of the association for molecular pathology. J Mol Diagn 13:7–11. https://doi.org/10.1016/j.jmoldx.2010.11.013
Narayanan S, Blumberg B, Clayman ML, Pan V, Wicklund C (2018) Exploring the issues surrounding clinical exome sequencing in the prenatal setting. J Genet Couns. https://doi.org/10.1007/s10897-018-0245-5
Norwitz ER, Levy B (2013) Noninvasive prenatal testing: the future is now. Rev Obstet Gynecol 6:48–62
Nuss S, Brebaum D, Grond-Ginsbach C (1994) Maternal cell contamination in amniotic fluid samples as a consequence of the sampling technique. Hum Genet 93:121–124
Palmor M, Fiester A (2014) Incidental findings of nonparentage: a case for universal nondisclosure. Pediatrics 134:163–168. https://doi.org/10.1542/peds.2013-4182
Pangalos C, Hagnefelt B, Lilakos K, Konialis C (2016) First applications of a targeted exome sequencing approach in fetuses with ultrasound abnormalities reveals an important fraction of cases with associated gene defects. PeerJ 4:e1955. https://doi.org/10.7717/peerj.1955
Park JY, Clark P, Londin E, Sponziello M, Kricka LJ, Fortina P (2015) Clinical exome performance for reporting secondary genetic findings. Clin Chem 61:213–220. https://doi.org/10.1373/clinchem.2014.231456
Rehm HL et al (2013) ACMG clinical laboratory standards for next-generation sequencing. Genet Med 15:733–747. https://doi.org/10.1038/gim.2013.92
Retterer K et al (2016) Clinical application of whole-exome sequencing across clinical indications. Genet Med 18:696–704. https://doi.org/10.1038/gim.2015.148
Richards S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424. https://doi.org/10.1038/gim.2015.30
Ross LF, Saal HM, David KL, Anderson RR, American Academy of P, American College of Medical G, Genomics (2013) Technical report: ethical and policy issues in genetic testing and screening of children. Genet Med 15:234–245. https://doi.org/10.1038/gim.2012.176
Sanghvi RV et al (2018) Characterizing reduced coverage regions through comparison of exome and genome sequencing data across 10 centers. Genet Med 20:855–866. https://doi.org/10.1038/gim.2017.192
Saunders CJ et al (2012) Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med 4:154ra. https://doi.org/10.1126/scitranslmed.3004041
Schrijver I et al (2012) Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology. J Mol Diagn 14:525–540. https://doi.org/10.1016/j.jmoldx.2012.04.006
Shendure J et al (2005) Accurate multiplex polony sequencing of an evolved bacterial genome. Science 309:1728–1732. https://doi.org/10.1126/science.1117389
Shettles LB (1971) Human blastocyst grown in vitro in ovulation cervical mucus. Nature 229:343
Soden SE et al (2014) Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med 6:265ra. https://doi.org/10.1126/scitranslmed.3010076
Soussi T, Leroy B, Devir M, Rosenberg S (2019) High prevalence of cancer-associated TP53 variants in the gnomAD database: a word of caution concerning the use of variant filtering. Hum Mutat 40:516–524. https://doi.org/10.1002/humu.23717
Steed HL, Tomkins DJ, Wilson DR, Okun N, Mayes DC (2002) Maternal cell contamination of amniotic fluid samples obtained by open needle versus trocar technique of amniocentesis. J Obstet Gynaecol Can 24:233–236
Steinberg S, Katsanis S, Moser A, Cutting G (2005) Biochemical analysis of cultured chorionic villi for the prenatal diagnosis of peroxisomal disorders: biochemical thresholds and molecular sensitivity for maternal cell contamination detection. J Med Genet 42:38–44. https://doi.org/10.1136/jmg.2004.023556
Stojilkovic-Mikic T, Mann K, Docherty Z, Mackie Ogilvie C (2005) Maternal cell contamination of prenatal samples assessed by QF-PCR genotyping. Prenat Diagn 25:79–83. https://doi.org/10.1002/pd.1089
Tankard RM, Bennett MF, Degorski P, Delatycki MB, Lockhart PJ, Bahlo M (2018) Detecting expansions of tandem repeats in cohorts sequenced with short-read sequencing data. Am J Hum Genet 103:858–873. https://doi.org/10.1016/j.ajhg.2018.10.015
Timmermans S, Buchbinder M (2010) Patients-in-waiting: living between sickness and health in the genomics era. J Health Soc Behav 51:408–423. https://doi.org/10.1177/0022146510386794
Venter JC et al (2001) The sequence of the human genome. Science 291:1304–1351. https://doi.org/10.1126/science.1058040
Vora NL et al (2017) Prenatal exome sequencing in anomalous fetuses: new opportunities and challenges. Genet Med 19:1207–1216. https://doi.org/10.1038/gim.2017.33
Voracek M, Haubner T, Fisher ML (2008) Recent decline in nonpaternity rates: a cross-temporal meta-analysis. Psychol Rep 103:799–811. https://doi.org/10.2466/pr0.103.3.799-811
Walknowska J, Conte FA, Grumbach MM (1969) Practical and theoretical implications of fetal–maternal lymphocyte transfer. Lancet (London, England) 1:1119–1122
Weida J et al (2017) Prevalence of maternal cell contamination in amniotic fluid samples. J Matern Fetal Neonatal Med 30:2133–2137. https://doi.org/10.1080/14767058.2016.1240162
Westerfield LE et al (2015) Reproductive genetic counseling challenges associated with diagnostic exome sequencing in a large academic private reproductive genetic counseling practice. Prenat Diagn 35:1022–1029. https://doi.org/10.1002/pd.4674
Whiffin N et al (2017) Using high-resolution variant frequencies to empower clinical genome interpretation. Genet Med 19:1151–1158. https://doi.org/10.1038/gim.2017.26
Willig LK et al (2015) Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med 3:377–387. https://doi.org/10.1016/S2213-2600(15)00139-3
Yang Y et al (2013) Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Engl J Med 369:1502–1511. https://doi.org/10.1056/NEJMoa1306555
Yang Y et al (2014) Molecular findings among patients referred for clinical whole-exome sequencing. Jama 312:1870–1879. https://doi.org/10.1001/jama.2014.14601
Yates CL et al (2017) Whole-exome sequencing on deceased fetuses with ultrasound anomalies: expanding our knowledge of genetic disease during fetal development. Genet Med 19:1171–1178. https://doi.org/10.1038/gim.2017.31
Yu N et al (2002) Disputed maternity leading to identification of tetragametic chimerism. N Engl J Med 346:1545–1552. https://doi.org/10.1056/NEJMoa013452
Yu Q, Li Q, Gao S, Su Y, Deng Z (2011) Congenital tetragametic blood chimerism explains a case of questionable paternity. J Forensic Sci 56:1346–1348. https://doi.org/10.1111/j.1556-4029.2011.01794.x
Zhao C et al (2015) Detection of fetal subchromosomal abnormalities by sequencing circulating cell-free DNA from maternal plasma. Clin Chem 61:608–616. https://doi.org/10.1373/clinchem.2014.233312
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We would like to acknowledge Matt Lebo, PhD and Kalotina Machini, PhD, CGC for critical review of the manuscript.
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Abou Tayoun, A., Mason-Suares, H. Considerations for whole exome sequencing unique to prenatal care. Hum Genet 139, 1149–1159 (2020). https://doi.org/10.1007/s00439-019-02085-7
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DOI: https://doi.org/10.1007/s00439-019-02085-7