[en] ("[en] PURPOSE: We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy.
METHODS: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy.
RESULTS: fCES identified the underlying genetic cause in 13% (24/183) of prospective and 29% (35/120) of retrospective cases. In both cohorts, recessive heterozygous compound genotypes were not rare, and trio and simplex variant analysis strategies were complementary to achieve the highest possible diagnostic rate. Limited prenatal phenotypic information led to interpretation challenges. In 2 prospective cases, in-depth analysis allowed expansion of the spectrum of prenatal presentations for genetic syndromes associated with the SLC17A5 and CHAMP1 genes.
CONCLUSION: fCES is diagnostically efficient in fetuses presenting with cerebral, skeletal, urinary, or multiple anomalies. The comparison between the 2 cohorts highlights the importance of providing detailed phenotypic information for better interpretation and prenatal reporting of genetic variants.","[en] ","")
Disciplines :
Genetics & genetic processes
Author, co-author :
Marangoni, Martina; Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: Martina.Marangoni@erasme.ulb.ac.be
Smits, Guillaume; Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Ceysens, Gilles; Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium, Department of Obstetrics and Gynecology, Hôpital Ambroise Paré, Mons, Belgium
Costa, Elena; Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Coulon, Robert; Department of Obstetrics and Gynecology, Centre Hospitalier EpiCURA, Ath, Belgium
Daelemans, Caroline; Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
De Coninck, Caroline; Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Derisbourg, Sara; Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Gajewska, Kalina; Department of Obstetrics and Gynecology, Hôpital Civil Marie Curie, Charleroi, Belgium
Garofalo, Giulia; Department of Fetal Medicine, CHU Saint-Pierre, Brussels, Belgium
Gounongbe, Caroline; Department of Fetal Medicine, CHU Saint-Pierre, Brussels, Belgium
Guizani, Meriem; Department of Fetal Medicine, CHU Saint-Pierre, Brussels, Belgium
Holoye, Anne; Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Houba, Catherine; Department of Fetal Medicine, CHU Saint-Pierre, Brussels, Belgium
Makhoul, Jean; Department of Gynecology and Obstetrics, Hôpitaux Iris Sud-Etterbeek-Ixelles, Brussels, Belgium
Norgaard, Christian; Department of Obstetrics and Gynecology, CHIREC - Braine-l'Alleud-Waterloo Hospital, Braine l'Alleud, Belgium
Regnard, Cecile; Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Romée, Stephanie; Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Soto, Jamil; Department of Gynecology and Obstetrics, Hôpitaux Iris Sud-Etterbeek-Ixelles, Brussels, Belgium
Stagel-Trabbia, Aurore; Department of Gynecology and Obstetrics, Hôpitaux Iris Sud-Etterbeek-Ixelles, Brussels, Belgium
Van Rysselberge, Michel; Department of Fetal Medicine, CHU Saint-Pierre, Brussels, Belgium
Vercoutere, An; Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Zaytouni, Siham; Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Bouri, Sarah; Department of Pathology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
D'Haene, Nicky; Department of Pathology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
D'Onle, Dominique; Department of Anatomopathology, Institut Jules Bordet, Brussels, Belgium
Dugauquier, Christian; Department of Pathology, Institut de Pathologie et de Génétique Gosselies, Charleroi, Belgium
Racu, Marie-Lucie; Department of Pathology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Rocq, Laureen; Department of Pathology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Segers, Valérie; Department of Anatomopathology, CHU Brugmann, Brussels, Belgium
Verocq, Camille; Department of Pathology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Avni, Ephraim Freddy; Department of Radiology, Hôpital Delta, Brussels, Belgium
Cassart, Marie; Department of Fetal Medicine, CHU Saint-Pierre, Brussels, Belgium, Department of Perinatal Imaging Radiology, Etterbeek-Ixelles Hospital, Brussels, Belgium
Massez, Anne; Department of Radiology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Blaumeiser, Bettina; Center for Medical Genetics, Universiteit en Universitair Ziekenhuis Antwerpen, Antwerp, Belgium
Brischoux-Boucher, Elise; Center of Human Genetics, Université de Franche-Comté, Besançon, France
BULK, Saskia ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
De Ravel, Thomy; Centre for Medical Genetics, Reproduction and Genetics, Reproduction Genetics and Regenerative Medicine, Vrije Universiteit Brussel (VUB), UZ Brussel, Brussels, Belgium
Debray, Guillaume; Center of Human Genetics, CHU de Liège, Liège, Belgium
Dimitrov, Boyan; Centre for Medical Genetics, Reproduction and Genetics, Reproduction Genetics and Regenerative Medicine, Vrije Universiteit Brussel (VUB), UZ Brussel, Brussels, Belgium
Janssens, Sandra; Center for Medical Genetics, University Hospital Ghent, Ghent, Belgium
Keymolen, Kathelijn; Centre for Medical Genetics, Reproduction and Genetics, Reproduction Genetics and Regenerative Medicine, Vrije Universiteit Brussel (VUB), UZ Brussel, Brussels, Belgium
Laterre, Marie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
van Berkel, Kim; Centre for Medical Genetics, Reproduction and Genetics, Reproduction Genetics and Regenerative Medicine, Vrije Universiteit Brussel (VUB), UZ Brussel, Brussels, Belgium
Van Maldergem, Lionel; Center of Human Genetics, Université de Franche-Comté, Besançon, France
Vandernoot, Isabelle; Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Vilain, Catheline; Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium, Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium
Donner, Catherine; Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
Tecco, Laura; Department of Fetal Medicine, CHU Saint-Pierre, Brussels, Belgium
Thomas, Dominique; Department of Gynecology and Obstetrics, Hôpitaux Iris Sud-Etterbeek-Ixelles, Brussels, Belgium
Désir, Julie; Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium, Center for Medical Genetics, Institut de Pathologie et de Génétique Gosselies, Charleroi, Belgium
Abramowicz, Marc; Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium, Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
Migeotte, Isabelle; Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium, Fonds de la Recherche Scientifique (FNRS), Brussels, Belgium. Electronic address: Isabelle.Migeotte@erasme.ulb.ac.be
The authors thank the parents and the referring physicians who contributed to this study. The authors acknowledge all the members of the Molecular Genetics Laboratory of the Hôpital Erasme for their valuable technical assistance. The authors thank the FNRS which supported M.M. through a FRIA-FNRS fellowship.The authors thank the parents and the referring physicians who contributed to this study. The authors acknowledge all the members of the Molecular Genetics Laboratory of the H?pital Erasme for their valuable technical assistance. The authors thank the FNRS which supported M.M. through a FRIA-FNRS fellowship. Conceptualization: M.M. G.S. J.D. M.A. I.M.; Data Curation: M.M.; Formal Analysis: M.M.; Investigation: M.M.; Methodology: M.M. G.S. C.V.; Resources: G.S. G.C. E.C. R.C. C.D. C.D.C. S.D. K.G. G.G. C.G. M.G. A.H. C.H. J.M. C.N. C.R. S.R. J.S. A.S.-T. M.V.R. A.V. S.Z. S.B. N.D'H. D.D'O. C.D. M.L.R. L.R. V.S. C.V. E.F.A. M.C. A.M. B.B. E.B.-B. S.B. T.D.R. G.D. B.D. S.J. K.K. M.L. K.v.B. L.V.M. I.V. C.V. C.D. L.T. D.T. M.A. J.D. I.M.; Supervision: G.S. J.D. M.A. I.M.; Visualization: M.M.; Writing-original draft: M.M.; Writing-review & editing: G.S. M.A. I.M. This study was approved by the ethical committee of the H?pital Erasme, Brussels, Belgium, under the reference P2016/236. Informed consent was obtained from all participants. This study adheres to the principles set out in the Declaration of Helsinki.
Calzolari, E., Barisic, I., Loane, M., et al. Epidemiology of multiple congenital anomalies in Europe: a EUROCAT population-based registry study. Birth Defects Res A Clin Mol Teratol 100:4 (2014), 270–276, 10.1002/bdra.23240.
Karim, J.N., Roberts, N.W., Salomon, L.J., Papageorghiou, A.T., Systematic review of first-trimester ultrasound screening for detection of fetal structural anomalies and factors that affect screening performance. Ultrasound Obstet Gynecol 50:4 (2017), 429–441, 10.1002/uog.17246.
Wapner, R.J., Martin, C.L., Levy, B., et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med 367:23 (2012), 2175–2184, 10.1056/NEJMoa1203382.
Callaway, J.L.A., Shaffer, L.G., Chitty, L.S., Rosenfeld, J.A., Crolla, J.A., The clinical utility of microarray technologies applied to prenatal cytogenetics in the presence of a normal conventional karyotype: a review of the literature. Prenat Diagn 33:12 (2013), 1119–1123, 10.1002/pd.4209.
Hillman, S.C., McMullan, D.J., Hall, G., et al. Use of prenatal chromosomal microarray: prospective cohort study and systematic review and meta-analysis. Ultrasound Obstet Gynecol 41:6 (2013), 610–620, 10.1002/uog.12464.
Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519:7542 (2015), 223–228, 10.1038/nature14135.
Lee, H., Deignan, J.L., Dorrani, N., et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA 312:18 (2014), 1880–1887, 10.1001/jama.2014.14604.
Retterer, K., Juusola, J., Cho, M.T., et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med 18:7 (2016), 696–704, 10.1038/gim.2015.148.
Yang, Y., Muzny, D.M., Reid, J.G., et al. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Engl J Med 369:16 (2013), 1502–1511, 10.1056/NEJMoa1306555.
Zhu, X., Petrovski, S., Xie, P., et al. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med 17:10 (2015), 774–781, 10.1038/gim.2014.191.
Drury, S., Williams, H., Trump, N., et al. Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities. Prenat Diagn 35:10 (2015), 1010–1017, 10.1002/pd.4675.
Normand, E.A., Braxton, A., Nassef, S., et al. Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder. Genome Med, 10(1), 2018, 74, 10.1186/s13073-018-0582-x.
Pangalos, C., Hagnefelt, B., Lilakos, K., Konialis, C., 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, 2016, e1955, 10.7717/peerj.1955.
Vora, N.L., Powell, B., Brandt, A., et al. Prenatal exome sequencing in anomalous fetuses: new opportunities and challenges. Genet Med 19:11 (2017), 1207–1216, 10.1038/gim.2017.33.
Yang, Y., Muzny, D.M., Xia, F., et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 312:18 (2014), 1870–1879, 10.1001/jama.2014.14601.
Lord, J., McMullan, D.J., Eberhardt, R.Y., et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet 393:10173 (2019), 747–757, 10.1016/S0140-6736(18)31940-8.
Petrovski, S., Aggarwal, V., Giordano, J.L., et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet 393:10173 (2019), 758–767, 10.1016/S0140-6736(18)32042-7.
Monaghan, K.G., Leach, N.T., Pekarek, D., Prasad, P., Rose, N.C., ACMG Professional Practice and Guidelines Committee. The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG). Genet Med 22:4 (2020), 675–680, 10.1038/s41436-019-0731-7.
Köhler, S., Vasilevsky, N.A., Engelstad, M., et al. The human phenotype ontology in 2017. Nucleic Acids Res 45:D1 (2017), D865–D876, 10.1093/nar/gkw1039.
Johansson, L.F., van Dijk, F., de Boer, E.N., et al. CoNVaDING: single exon variation detection in targeted NGS data. Hum Mutat 37:5 (2016), 457–464, 10.1002/humu.22969.
Richards, S., Aziz, N., Bale, S., 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 17:5 (2015), 405–424, 10.1038/gim.2015.30.
Kalia, S.S., Adelman, K., Bale, S.J., et al. 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 19:2 (2017), 249–255 Published correction appears in Genet Med. 2017;19(4):484 https://doi.org/10.1038/gim.2016.190.
Daum, H., Meiner, V., Elpeleg, O., Harel, T., Collaborating Authors. Fetal exome sequencing: yield and limitations in a tertiary referral center. Ultrasound Obstet Gynecol 53:1 (2019), 80–86, 10.1002/uog.19168.
Wright, C.F., McRae, J.F., Clayton, S., et al. Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders. Genet Med 20:10 (2018), 1216–1223, 10.1038/gim.2017.246.
de Koning, M.A., Haak, M.C., Adama van Scheltema, P.N., et al. From diagnostic yield to clinical impact: a pilot study on the implementation of prenatal exome sequencing in routine care. Genet Med 21:10 (2019), 2303–2310, 10.1038/s41436-019-0499-9.
Becher, N., Andreasen, L., Sandager, P., et al. Implementation of exome sequencing in fetal diagnostics-Data and experiences from a tertiary center in Denmark. Acta Obstet Gynecol Scand 99:6 (2020), 783–790, 10.1111/aogs.13871.
Sukenik-Halevy, R., Ruhrman-Shahar, N., Orenstein, N., et al. The diagnostic efficacy of exome data analysis using fixed neurodevelopmental gene lists: implications for prenatal setting. Prenat Diagn 41:6 (2021), 701–707, 10.1002/pd.5929.
De Graer, C., Marangoni, M., Romnée, S., et al. Novel features of PIK3CA-Related Overgrowth Spectrum: lesson from an aborted fetus presenting a de novo constitutional PIK3CA mutation. Eur J Med Genet, 63(4), 2020, 103775, 10.1016/j.ejmg.2019.103775.
Gounongbé, C., Marangoni, M., Gouder de Beauregard, V., et al. Middle interhemispheric variant of holoprosencephaly: first prenatal report of a ZIC2 missense mutation. Clin Case Rep 8:7 (2020), 1287–1292, 10.1002/ccr3.2896.
