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Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations
  1. Mathilde Lefebvre1,2,
  2. Ange-Line Bruel1,3,
  3. Emilie Tisserant1,
  4. Nicolas Bourgon1,
  5. Yannis Duffourd1,
  6. Sophie Collardeau-Frachon4,
  7. Tania Attie-Bitach5,
  8. Paul Kuentz1,
  9. Mirna assoum1,
  10. Elise Schaefer6,
  11. Salima El Chehadeh6,
  12. Maria Cristina Antal7,
  13. Valérie Kremer8,
  14. Françoise Girard-Lemaitre9,
  15. Jean-Louis Mandel9,
  16. Daphne Lehalle10,
  17. Sophie Nambot10,
  18. Nolwenn Jean-Marçais10,
  19. Nada Houcinat10,
  20. Sébastien Moutton1,10,
  21. Nathalie Marle11,
  22. Laetita Lambert12,
  23. Philippe Jonveaux13,
  24. Bernard Foliguet14,
  25. Jean-Pierre Mazutti14,
  26. Dominique Gaillard15,
  27. Elisabeth Alanio15,
  28. Celine Poirisier16,
  29. Anne-Sophie Lebre17,
  30. Marion Aubert-Lenoir18,
  31. Francine Arbez-Gindre19,
  32. Sylvie Odent20,
  33. Chloé Quélin20,21,
  34. Philippe Loget21,
  35. Melanie Fradin20,
  36. Marjolaine Willems22,
  37. Nicole Bigi23,
  38. Marie-José Perez23,
  39. Sophie Blesson24,
  40. Christine Francannet25,
  41. Anne-Marie Beaufrere26,
  42. Sophie Patrier-Sallebert27,
  43. Anne-Marie Guerrot28,
  44. Alice Goldenberg28,
  45. Anne-Claire Brehin28,
  46. James Lespinasse29,
  47. Renaud Touraine30,
  48. Yline Capri31,
  49. Marie-Hélène Saint-Frison32,
  50. Nicole Laurent2,
  51. Christophe Philippe1,3,
  52. Frederic Tran Mau-them1,3,
  53. Julien Thevenon1,33,
  54. Laurence Faivre1,10,
  55. Christel Thauvin-Robinet1,3,34,
  56. Antonio Vitobello1,3
  1. 1UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD « Génétique des Anomalies du Développement », FHU-TRANSLAD, Dijon, France
  2. 2Laboratoire d’Anatomo-Pathologie, Plateforme de Biologie Hospitalo-Universitaire, CHU de Dijon Bourgogne, Dijon, France
  3. 3Unité Fonctionnelle d’Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France
  4. 4Département d’Anatomo-pathologie, Hospices Civils de Lyon, Lyon, France
  5. 5Laboratoire d’Embryologie et de Génétique des Malformations Congénitales, Hopital Necker, APHP, Paris Cedex 15, France
  6. 6Service de Génétique Médicale, CHU de Strasbourg, Hôpital de Hautepierre, Strasbourg, France
  7. 7Service de Fœtopathologie, CHU de Strasbourg, Hôpital de Hautepierre, Strasbourg, France
  8. 8Laboratoire de Cytogénétique constitutionnelle et prénatale, CHU de Strasbourg, Strasbourg, France
  9. 9Département Médecine translationnelle et neurogénétique, Institut de génétique et de biologie moléculaire et cellulaire, Strasbourg, France
  10. 10Centre de Référence Maladies Rares « Anomalies du Développement et Syndrome Malformatifs » de L'Est, Hôpital D'Enfants, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France
  11. 11Laboratoire de Génétique chromosomique et moléculaire, CHU de Dijon Bourgogne, Dijon, France
  12. 12UF de Génétique médicale, Maternité régionale, CHU de Nancy, Nancy, France
  13. 13Laboratoire de Génétique médicale, CHU de Nancy, Nancy, France
  14. 14Laboratoire de Biologie de la Reproduction et du Développement Maternité de Nancy, CHU de Nancy, Nancy, France
  15. 15Service de Foetopathologie, CHU de Reims, Reims, France
  16. 16Laboratoire de Cytogénétique, CHU de Reims, Reims, France
  17. 17Service de Génétique et Biologie de la Reproduction, CHU de Reims, Reims, France
  18. 18Service d’Imagerie médicale, CHU de Besançon, Besançon, France
  19. 19Service de Fœtopathologie, CHU de Besançon, Besançon, France
  20. 20Service de Génétique Clinique, Hôpital Sud, CLAD Ouest, CNRS UMR6290 Génétique et Pathologies du Développement, Université de Rennes, Rennes, France
  21. 21Service de Fœtopathologie, CHU de Rennes, Rennes, France
  22. 22Equipe Maladies Génétiques de l'Enfant et de l'Adulte, CHU de Montpellier, Montpellier, France
  23. 23Service de Fœtopathologie, CHU de Montpellier, Montpellier, France
  24. 24Service de Génétique, CHU de Tours, Tours, France
  25. 25Service de Génétique médicale, CHU de Clermont-Ferrand, Clermont-Ferrand, France
  26. 26Service de Fœtopathologie, CHU de Clermont-Ferrand, Clermont-Ferrand, France
  27. 27Service de Fœtopathologie, CHU de Rouen, Rouen, France
  28. 28Service de Génétique clinique, CHU de Rouen, Rouen, France
  29. 29Service de Génétique clinique, CH de Chambéry, Chambéry, France
  30. 30Service de Genetique Clinique, C.H.U. De Saint Etienne-Hopital Nord, Saint Etienne Cedex 2, France
  31. 31Service de génétique clinique, Hôpital Robert Debré - APHP, Paris, France
  32. 32Service de foetopathologie, Hôpital Robert Debré - APHP, Paris, France
  33. 33Département de Génétique et Procréation, CHU Grenoble Alpes, Université Grenoble Alpes, Grenoble, France
  34. 34Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital D'Enfants, CHU Dijon Bourgogne, Dijon, France
  1. Correspondence to Dr Antonio Vitobello, UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD, FHU-TRANSLAD, Bâtiment B3, 15 avenue du maréchal Delattre de Tassigny, 21000, Dijon, France; antonio.vitobello{at}; Dr Christel Thauvin-Robinet, Centre de Référence Déficiences Intellectuelles de Causes Rares, Hôpital D'Enfants, CHU Dijon Bourgogne, 21000, Dijon, France; christel.thauvin{at}


Purpose Molecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.

Methods We performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and bioinformatics predictions followed by reverse phenotyping. Initially applied to OMIM-morbid genes, analyses were then extended to all genes. We complemented our approach by using reverse phenotyping, variant segregation analysis, bibliographic search and data sharing in order to establish the clinical significance of the prioritised variants.

Results sES rapidly identified causal variant in 24/95 fetuses (25%), variants of unknown significance in OMIM genes in 8/95 fetuses (8%) and six novel candidate genes in 6/95 fetuses (6%).

Conclusions This method, based on a genotype-first approach followed by reverse phenotyping, shed light on unexpected fetal phenotype-genotype correlations, emphasising the relevance of prenatal studies to reveal extreme clinical presentations associated with well-known Mendelian disorders.

  • genetics
  • molecular genetics
  • reproductive medicine
  • complex traits
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  • CT-R and AV are joint senior authors.

  • ML and A-LB are joint first authors.

  • ML and A-LB contributed equally.

  • Contributors ML performed some autopsy, analysed exome data, shared part of the data, wrote and submitted the manuscript. ALB analysed exome date and shared part of the data. AV and CTR co-directed the work.ET and YD performed bioinformatics analysis. NBo, PK, MA, CP, FTMT and JT analysed exome data. SCF and TAB gave expert advice on fetal phenotypes. MCA, BF, JPM, DG, FAG, EA, CQ, PL, NBi, MJP, SB, AMB, SP, ACB, MHS and NL performed the autopsy and gave frozen tissue. ES, SEC, DL, SN, NJM, NH, SM, LL, MAL, SO, MF, MW, CQ, CF, AMG, AG, JL, RT, YC and LF followed the patient, prescribed genetics investigation and gave patient data. VK, FGL, JLM, NM, PJ, CP and ASL performed cytogenetics test. CT-­R and AV are last authors.

  • Funding This study was funded by Interregional French PHRC Interregional 14-013 FOETEX.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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