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  • Print publication year: 2020
  • Online publication date: October 2019

Chapter 4 - Human Genetics and Fetal Disease: Assessment of the Fetal Genome

from Section 1: - General Principles


Structural fetal anomalies complicate up to 5% of pregnancies and an underlying chromosomal or genetic etiology underlies up to half of cases. Understanding the fetal genome is increasingly key in attempting to make a prenatal diagnosis and in delineating a prognosis for the baby. Over the past decades, the field of prenatal genomics has advanced exponentially, beginning with the conventional ‘full’ karyotype available in the 1960s and going up to the present day and beyond with the application of next-generation sequencing (NGS) (Figure 4.1). Current and potential future advances in prenatal diagnostics will allow couples to make more informed decisions prospectively about their pregnancies in addition to aiding decisions on and the development of fetal therapies [1]. In the wake of advancing technologies and large prospective studies such as the United Kingdom’s ‘proof of principle’ 100 000 Genomes Project [2] and the Prenatal Assessment of Genomes and Exomes (PAGE) study [3], the degree of information obtained and turnaround time of results with the development of more sophisticated bioinformatic analytical pathways is likely to improve rapidly. Fetal medicine subspecialists, obstetricians, pediatricians, geneticists, genomic scientists and genetic counselors have a responsibility to stay up to date with this wealth of advances so that couples can be informed accordingly.

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[1]Horn, R, Parker, M. Opening Pandora’s box?: ethical issues in prenatal whole genome and exome sequencing. Prenat Diagn. 2018; 38: 2025.
[2]Genomics England. 2018. 100,000 Genomes Project.
[3]Lord, J, McMullan, DJ, Eberhardt, RY, Rinck, G, Hamilton, SJ, Quinlan-Jones, E, et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet. 2019; 393: 747–57.
[4]Fetal Anomaly Screening Programme Handbook. London: Public Health England, 2018.
[5]Nicolaides, KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J Obstet Gynecol. 2004; 191: 4567.
[22]Wolfson Institute of Preventive Medicine. The Combined Test.
[6]Chiu, RW, Lo, YM. Clinical applications of maternal plasma fetal DNA analysis: translating the fruits of 15 years of research. Clin Chem Lab Med. 2013; 51: 197204.
[7]Gil, MM, Brik, M, Casanova, C, Martin-Alonso, R, Verdejo, M, Ramírez, E, Santacruz, B. Screening for trisomies 21 and 18 in a Spanish public hospital: from the combined test to the cell-free DNA test. J Matern Fetal Neonatal Med. 2017; 30: 2476–82.
[8]Vinante, V, Keller, B, Huhn, EA, Huang, D, Lapaire, O, Manegold-Brauer, G. Impact of nationwide health insurance coverage for non-invasive prenatal testing. Int J Gynaecol Obstet. 2018; 141: 189–93.
[9]Lewis, C, Hill, M, Silcock, C, Daley, R, Chitty, LS. Non-invasive prenatal testing for trisomy 21: a cross-sectional survey of service users’ views and likely uptake. BJOG. 2014; 121: 582–94.
[10]Mackie, FL, Hemming, K, Allen, S, Morris, RK, Kilby, MD. The accuracy of cell-free fetal DNA-based non-invasive prenatal testing in singleton pregnancies: a systematic review and bivariate meta-analysis. BJOG. 2017; 124: 3246.
[11]Gil, MM, Accurti, V, Santacruz, B, Plana, MN, Nicolaides, KH. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2017; 50: 302–14.
[12]Hui, L, Tabor, A, Walker, SP, Kilby, MD. How to safeguard competency and training in invasive prenatal diagnosis: ‘the elephant in the room’. Ultrasound Obstet Gynecol. 2016; 47: 813.
[13]Persson, M, Cnattingius, S, Villamor, E, Söderling, J, Pasternak, B, Stephansson, O, Neovius, M. Risk of major congenital malformations in relation to maternal overweight and obesity severity: cohort study of 1.2 million singletons. BMJ. 2017; 357: j2563.
[14]Chitty, LS. Cell-free DNA testing: an aid to prenatal sonographic diagnosis. Best Pract Res Clin Obstet Gynaecol. 2014 ; 28 : 453–66.
[15]Ogilvie, CM, Lashwood, A, Chitty, L, Waters, JJ, Scriven, PN, Flinter, F. The future of prenatal diagnosis: rapid testing or full karyotype? An audit of chromosome abnormalities and pregnancy outcomes for women referred for Down’s Syndrome testing. BJOG. 2005; 112: 1369–75.
[16]Stosic, M, Levy, B, Wapner, R. The Use of Chromosomal Microarray Analysis in Prenatal Diagnosis. Obstet Gynecol Clin North Am. 2018; 45: 5568.
[17]Best, S, Wou, K, Vora, N, Van der Veyver, IB, Wapner, R, Chitty, LS. Promises, pitfalls and practicalities of prenatal whole exome sequencing. Prenat Diagn. 2018; 38: 1019.
[18]International Society for Prenatal Diagnosis, Society for Maternal Fetal Medicine, Perinatal Quality Foundation. 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. 2018; 38: 69.
[19]Luthardt, FW, Keitges, E. Chromosomal Syndromes and Genetic Disease. In Encyclopedia of Life Sciences. Chichester: John Wiley & Sons, 2001.
[20]Nadler, HL, Gerbie, AB. Role of amniocentesis in the intrauterine detection of genetic disorders. N Engl J Med. 1970; 282: 596–9.
[21]Nicolini, U, Lalatta, F, Natacci, F, Curcio, C, Bui, TH. The introduction of QF-PCR in prenatal diagnosis of fetal aneuploidies: time for reconsideration. Hum Reprod Update. 2004; 10: 541–8.
[23]Ockeloen, CW, Willemsen, MH, de Munnik, S, van Bon, BW, de Leeuw, N, Verrips, A, et al. Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations. Eur J Hum Genet. 2015; 23: 1176–85.
[24]Hillman, SC, McMullan, DJ, Hall, G, Togneri, FS, James, N, Maher, EJ, et al. Use of prenatal chromosomal microarray: prospective cohort study and systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2013; 41: 610–20.
[25]Robson, SC, Chitty, LS, Morris, S, Verhoef, T, Ambler, G, Wellesley, DG, et al. Evaluation of array comparative genomic hybridisation in prenatal diagnosis of fetal anomalies: a multicentre cohort study with cost analysis and assessment of patient, health professional and commissioner preferences for array comparative genomic hybridisation. Efficacy Mech Eval. 2017; 4(1).
[26]Hillman, SC, McMullan, DJ, Silcock, L, Maher, ER, Kilby, MD. How does altering the resolution of chromosomal microarray analysis in the prenatal setting affect the rates of pathological and uncertain findings? J Matern Fetal Neonatal Med. 2014; 27: 649–57.
[27]Wapner, RJ, Levy, B, Ballif, BC, Eng, CM, Zachary, JM, Savage, M, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012; 367: 2175–84.
[28]Wapner, RJ, Zachary, J, Clifton, R. Change in classification of prenatal microarray analysis copy number variants over time [abstract]. Prenat Diagn. 2015; 35 (Suppl. S1): 126.
[29]Xia, Y, Yang, Y, Huang, S, Wu, Y, Li, P, Zhuang, J. Clinical application of chromosomal microarray analysis for the prenatal diagnosis of chromosomal abnormalities and copy number variations in fetuses with congenital heart disease. Prenat Diagn. 2018; 38: 406413.
[30]Egloff, M, Hervé, B, Quibel, T, Jaillard, S, Le Bouar, G, Uguen, K, et al. Diagnostic yield of chromosomal microarray analysis in fetuses with increased nuchal translucency: a French multicenter retrospective study. Ultrasound Obstet Gynecol. 2017; 52: 715–21.
[31]Richards, S, Aziz, N, Bale, S, Bick, D, Das, S, Gastier-Foster, J, et al. 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. 2015; 17: 405–24.
[32]Society for Maternal-Fetal Medicine (SMFM). The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol. 2016; 215: B2–9.
[33]American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol. 2013; 122: 1374–7.
[34]Armour, CM, Dougan, SD, Brock, JA, Chari, R, Chodirker, BN, DeBie, I, et al. Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada. J Med Genet. 2018; 55: 215221.
[35]Gardiner, C, Wellesley, D, Kilby, MD, Bronwyn, K, on behalf of the Joint Committee on Genomics in Medicine (2015). G144: Recommendations for the use of chromosome microarray in pregnancy.
[36]Yang, Y, Muzny, DM, Reid, JG, Bainbridge, MN, Willis, A, Ward, PA, et al. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Eng J Med. 2013; 369: 1502–12.
[37]Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015; 519: 223–8.
[38]Ku, CS, Naidoo, N, Pawitan, Y. Revisiting Mendelian disorders through exome sequencing. Hum Genet. 2011; 129: 351–70.
[39]Chandler, N, Best, S, Hayward, J, Faravelli, F, Mansour, S, Kivuva, E, et al. Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management. Genet Med. 2018; 20: 1430–7.
[40]Quinlan-Jones, E, Lord, J, Williams, D, Hamilton, S, Marton, T, Eberhardt, RY, et al. Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies. Genet Med. 2018; 21: 1065–73.
[41]Carss, KJ, Hillman, SC, Parthiban, V, McMullan, DJ, Maher, ER, Kilby, MD, Hurles, ME. Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound. Hum Mol Genet. 2014; 23: 3269–77.
[42]Talkowski, ME, Ordulu, Z, Pillalamarri, V, Benson, CB, Blumenthal, I, Connolly, S, et al. Clinical diagnosis by whole-genome sequencing of a prenatal sample. N Engl J Med. 2012; 367: 2226–32.
[43]Bodian, DL, Klein, E, Iyer, RK, Wong, WS, Kothiyal, P, Stauffer, D, et al. Utility of whole-genome sequencing for detection of newborn screening disorders in a population cohort of 1,696 neonates. Genet Med. 2016; 18: 221–30.
[44]American College of Obstetricians & Gynecologists Committee on Genetics. Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstet Gynecol. 2013; 122: 1374–7
[45]Joint Committee on Medical Genetics (2011). Consent and confidentiality in clinical genetic practice: Guidance on genetic testing and sharing genetic information.