M Egloff1,2, B Hervé3,4, T Quibel5, S Jaillard6, G Le Bouar7, K Uguen8, A-H Saliou9, M Valduga10, E Perdriolle11, C Coutton12, A-L Coston13, A Coussement14, O Anselem15, C Missirian16, F Bretelle17, F Prieur18, C Fanget19, C Muti20, M-C Jacquemot21, C Beneteau22, C Le Vaillant23, M Vekemans1,2, L J Salomon2,24, F Vialard3,4, V Malan1,2. 1. Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, APHP, Paris, France. 2. Sorbonne Paris Cité, Université Paris Descartes, Paris, France. 3. Unité de Cytogénétique, CHI de Poissy St Germain, Poissy, France. 4. EA7404-GIG, UFR des Sciences de la Santé Simone Veil, UVSQ, Montigny-le-Bretonneux, France. 5. Service de Gynécologie Obstétrique, CHI de Poissy St Germain, Poissy, France. 6. Service de Cytogénétique et Biologie Cellulaire, CHU de Rennes, Rennes, France. 7. Département de Gynécologie Obstétrique et Reproduction Humaine, CHU de Rennes, Rennes, France. 8. Laboratoire de Cytogénétique, Cytologie et Biologie de la Reproduction, CHRU, Brest, France. 9. Centre Pluridisciplinaire de Diagnostic Prénatal, CHRU, Brest, France. 10. Service de Génétique, CHRU Nancy-Brabois, Nancy, France. 11. Service d'Obstétrique, CHRU Nancy-Brabois, Nancy, France. 12. Laboratoire de Génétique Chromosomique, INSERM 1209, CNRS UMR 5309, CHU Grenoble Alpes, Institut Albert Bonniot, Université Grenoble Alpes, Grenoble, France. 13. Service de Gynécologie-Obstétrique et Médecine de la Reproduction, Hôpital Couple Enfant, Université Grenoble Alpes, CHU Grenoble Alpes, Grenoble, France. 14. Laboratoire de Cytogénétique, Hôpital Cochin, APHP, Paris, France. 15. Service de Gynécologie et Obstétrique de Port-Royal, Maternité Port-Royal, Groupe Hospitalier Cochin Broca Hôtel-Dieu, APHP, Paris, France. 16. Département de Génétique Médicale, CHU Timone Enfants, APHM, Marseille, France. 17. Service de Gynécologie Obstétrique, CHU Nord, APHM, Marseille, France. 18. Service de Génétique Clinique Chromosomique Moléculaire, CHU Saint-Etienne, Saint-Etienne, France. 19. Service d'Obstétrique, CHU Saint-Etienne, Saint-Etienne, France. 20. Génétique Constitutionnelle, Laboratoire de Biologie, Centre Hospitalier de Versailles, Le Chesnay, France. 21. Consultation de Diagnostic Prénatal, Service de Gynécologie Obstétrique, Centre Hospitalier de Versailles, Le Chesnay, France. 22. Service de Génétique Médicale, CHU Nantes, Nantes, France. 23. Service de Gynécologie-Obstétrique, CHU de Nantes, Nantes, France. 24. Service d'Obstétrique, Hôpital Necker-Enfants Malades, APHP, Paris, France.
Abstract
OBJECTIVE: To determine the frequency and nature of copy number variants (CNVs) identified by chromosomal microarray analysis (CMA) in a large cohort of fetuses with isolated increased nuchal translucency thickness (NT) ≥ 3.5 mm. METHODS: This was a retrospective, multicenter study, including 11 French hospitals, of data from the period between April 2012 and December 2015. In total, 720 fetuses were analyzed by rapid aneuploidy test and the fetuses identified as euploid underwent CMA. CNVs detected were evaluated for clinical significance and classified into five groups: pathogenic CNVs; benign CNVs; CNVs predisposing to neurodevelopmental disorders; variants of uncertain significance (VOUS); and CNVs not related to the phenotype (i.e. incidental findings). RESULTS: In 121 (16.8%) fetuses, an aneuploidy involving chromosome 13, 18 or 21 was detected by rapid aneuploidy test and the remaining 599 fetuses were euploid. Among these, 53 (8.8%) had a CNV detected by CMA: 16/599 (2.7%) were considered to be pathogenic, including 11/599 (1.8%) that were cryptic (not visible by karyotyping); 7/599 (1.2%) were CNVs predisposing to neurodevelopmental disorders; and 8/599 (1.3%) were VOUS. Additionally, there was one (0.2%) CNV that was unrelated to the reason for referral diagnosis (i.e. an incidental finding) and the remaining 21 were benign CNVs, without clinical consequence. Interestingly, we identified five genomic imbalances of the 1q21.1 or 15q11.2 regions known to be associated with congenital heart defects. CONCLUSION: Our study demonstrates the benefit of CMA in the etiological diagnosis of fetuses with isolated increased NT. It is worth noting that most (69%) of the detected pathogenic CNVs were cryptic.
OBJECTIVE: To determine the frequency and nature of copy number variants (CNVs) identified by chromosomal microarray analysis (CMA) in a large cohort of fetuses with isolated increased nuchal translucency thickness (NT) ≥ 3.5 mm. METHODS: This was a retrospective, multicenter study, including 11 French hospitals, of data from the period between April 2012 and December 2015. In total, 720 fetuses were analyzed by rapid aneuploidy test and the fetuses identified as euploid underwent CMA. CNVs detected were evaluated for clinical significance and classified into five groups: pathogenic CNVs; benign CNVs; CNVs predisposing to neurodevelopmental disorders; variants of uncertain significance (VOUS); and CNVs not related to the phenotype (i.e. incidental findings). RESULTS: In 121 (16.8%) fetuses, an aneuploidy involving chromosome 13, 18 or 21 was detected by rapid aneuploidy test and the remaining 599 fetuses were euploid. Among these, 53 (8.8%) had a CNV detected by CMA: 16/599 (2.7%) were considered to be pathogenic, including 11/599 (1.8%) that were cryptic (not visible by karyotyping); 7/599 (1.2%) were CNVs predisposing to neurodevelopmental disorders; and 8/599 (1.3%) were VOUS. Additionally, there was one (0.2%) CNV that was unrelated to the reason for referral diagnosis (i.e. an incidental finding) and the remaining 21 were benign CNVs, without clinical consequence. Interestingly, we identified five genomic imbalances of the 1q21.1 or 15q11.2 regions known to be associated with congenital heart defects. CONCLUSION: Our study demonstrates the benefit of CMA in the etiological diagnosis of fetuses with isolated increased NT. It is worth noting that most (69%) of the detected pathogenic CNVs were cryptic.
Authors: Katarzyna Kowalczyk; Magdalena Bartnik-Głaska; Marta Smyk; Izabela Plaskota; Joanna Bernaciak; Marta Kędzior; Barbara Wiśniowiecka-Kowalnik; Marta Deperas; Justyna Domaradzka; Alicja Łuszczek; Daria Dutkiewicz; Agata Kozar; Dominika Grad; Magdalena Niemiec; Kamila Ziemkiewicz; Róża Magdziak; Natalia Braun-Walicka; Artur Barczyk; Maciej Geremek; Jennifer Castañeda; Anna Kutkowska-Kaźmierczak; Paweł Własienko; Krystyna Jakubów-Durska; Marzena Dębska; Anna Kucińska-Chahwan; Szymon Kozłowski; Boyana Mikulska; Tadeusz Issat; Tomasz Roszkowski; Agnieszka Nawara-Baran; Agata Runge; Anna Jakubiuk-Tomaszuk; Anna Kruczek; Ewa Kostyk; Grzegorz Pietras; Janusz Limon; Jerzy Zwoliński; Karolina Ochman; Tomasz Szajner; Piotr Węgrzyn; Mirosław Wielgoś; Maria Sąsiadek; Ewa Obersztyn; Beata Anna Nowakowska Journal: Genes (Basel) Date: 2022-04-14 Impact factor: 4.141