Martina Marangoni1, Guillaume Smits2, Gilles Ceysens3, Elena Costa4, Robert Coulon5, Caroline Daelemans4, Caroline De Coninck4, Sara Derisbourg4, Kalina Gajewska6, Giulia Garofalo7, Caroline Gounongbe7, Meriem Guizani7, Anne Holoye4, Catherine Houba7, Jean Makhoul8, Christian Norgaard9, Cecile Regnard4, Stephanie Romée4, Jamil Soto8, Aurore Stagel-Trabbia8, Michel Van Rysselberge7, An Vercoutere4, Siham Zaytouni4, Sarah Bouri10, Nicky D'Haene10, Dominique D'Onle11, Christian Dugauquier12, Marie-Lucie Racu10, Laureen Rocq10, Valérie Segers13, Camille Verocq10, Ephraim Freddy Avni14, Marie Cassart15, Anne Massez16, Bettina Blaumeiser17, Elise Brischoux-Boucher18, Saskia Bulk19, Thomy De Ravel20, Guillaume Debray19, Boyan Dimitrov20, Sandra Janssens21, Kathelijn Keymolen20, Marie Laterre19, Kim van Berkel20, Lionel Van Maldergem18, Isabelle Vandernoot2, Catheline Vilain22, Catherine Donner4, Laura Tecco7, Dominique Thomas8, Julie Désir23, Marc Abramowicz24, Isabelle Migeotte25. 1. Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: Martina.Marangoni@erasme.ulb.ac.be. 2. Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 3. Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Department of Obstetrics and Gynecology, Hôpital Ambroise Paré, Mons, Belgium. 4. Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 5. Department of Obstetrics and Gynecology, Centre Hospitalier EpiCURA, Ath, Belgium. 6. Department of Obstetrics and Gynecology, Hôpital Civil Marie Curie, Charleroi, Belgium. 7. Department of Fetal Medicine, CHU Saint-Pierre, Brussels, Belgium. 8. Department of Gynecology and Obstetrics, Hôpitaux Iris Sud-Etterbeek-Ixelles, Brussels, Belgium. 9. Department of Obstetrics and Gynecology, CHIREC - Braine-l'Alleud-Waterloo Hospital, Braine l'Alleud, Belgium. 10. Department of Pathology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 11. Department of Anatomopathology, Institut Jules Bordet, Brussels, Belgium. 12. Department of Pathology, Institut de Pathologie et de Génétique Gosselies, Charleroi, Belgium. 13. Department of Anatomopathology, CHU Brugmann, Brussels, Belgium. 14. Department of Radiology, Hôpital Delta, Brussels, Belgium. 15. Department of Fetal Medicine, CHU Saint-Pierre, Brussels, Belgium; Department of Perinatal Imaging Radiology, Etterbeek-Ixelles Hospital, Brussels, Belgium. 16. Department of Radiology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 17. Center for Medical Genetics, Universiteit en Universitair Ziekenhuis Antwerpen, Antwerp, Belgium. 18. Center of Human Genetics, Université de Franche-Comté, Besançon, France. 19. Center of Human Genetics, CHU de Liège, Liège, Belgium. 20. Centre for Medical Genetics, Reproduction and Genetics, Reproduction Genetics and Regenerative Medicine, Vrije Universiteit Brussel (VUB), UZ Brussel, Brussels, Belgium. 21. Center for Medical Genetics, University Hospital Ghent, Ghent, Belgium. 22. Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium. 23. 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. 24. 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. 25. 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.
Abstract
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.
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.
Authors: Anna Kucińska-Chahwan; Maciej Geremek; Tomasz Roszkowski; Julia Bijok; Diana Massalska; Michał Ciebiera; Hildeberto Correia; Iris Pereira-Caetano; Ana Barreta; Ewa Obersztyn; Anna Kutkowska-Kaźmierczak; Paweł Własienko; Małgorzata Krajewska-Walasek; Piotr Węgrzyn; Lech Dudarewicz; Waldemar Krzeszowski; Magda Rybak-Krzyszkowska; Beata Nowakowska Journal: Genes (Basel) Date: 2022-04-21 Impact factor: 4.141