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16p13.11 microduplication in 45 new patients: refined clinical significance and genotype–phenotype correlations
  1. Laïla Allach El Khattabi1,2,31,
  2. Solveig Heide1,
  3. Jean-Hubert Caberg3,
  4. Joris Andrieux4,
  5. Martine Doco Fenzy5,
  6. Caroline Vincent-Delorme6,
  7. Patrick Callier7,
  8. Sandra Chantot-Bastaraud8,
  9. Alexandra Afenjar9,
  10. Odile Boute-Benejean10,
  11. Marie Pierre Cordier11,
  12. Laurence Faivre7,
  13. Christine Francannet12,
  14. Marion Gerard13,
  15. Alice Goldenberg14,
  16. Alice Masurel-Paulet7,
  17. Anne-Laure Mosca-Boidron7,
  18. Nathalie Marle7,
  19. Anne Moncla15,
  20. Nathalie Le Meur16,
  21. Michèle Mathieu-Dramard17,
  22. Ghislaine Plessis13,
  23. Gaetan Lesca11,18,
  24. Massimiliano Rossi11,18,
  25. Patrick Edery11,18,
  26. Andrée Delahaye-Duriez19,20,
  27. Loïc De Pontual21,
  28. Anne Claude Tabet22,
  29. Aziza Lebbar1,
  30. Lesley Suiro23,
  31. Christine Ioos23,
  32. Abdelhafid Natiq24,
  33. Siham Chafai Elalaoui24,
  34. Chantal Missirian15,
  35. Aline Receveur25,
  36. Caroline François-Fiquet26,
  37. Pascal Garnier27,
  38. Catherine Yardin28,
  39. Cécile Laroche29,
  40. Philippe Vago30,
  41. Damien Sanlaville11,18,
  42. Jean Michel Dupont1,2,
  43. Brigitte Benzacken19,
  44. Eva Pipiras19
  1. 1 Cytogenetics department, Cochin Hospital, Assistance Publique des Hôpitaux de Paris; Sorbonne Paris Cité, Paris Descartes University, Medical school, Paris, France
  2. 2 Department of Development, Reproduction and Cancer, Cochin Research Institute, INSERM U1016, CNRS UMR8104, Paris, France
  3. 3 Genetics department, CHU de Liège - UniLab Lg, Liège, Belgium
  4. 4 Genetics department, Jeanne de Flandre Hospital, CHRU de Lille, Lille, France
  5. 5 Genetics department, CHU Reims, Medical school IFR53, EA3801, Reims, France
  6. 6 Genetics department, Guy Fontaine Medical center, CLAD Nord de France, Jeanne de Flandre Hospital, CHRU Lille, CH Arras, Arras, France
  7. 7 Genetics department, CHU de Dijon, Dijon, France
  8. 8 Genetics and Embryology department, Armand-Trousseau Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France
  9. 9 Neuropediatrics department, Armand-Trousseau Hospital, Assistance Publique des Hôpitaux de Paris; Reference Center for cerebellar malformations, Paris, France
  10. 10 Genetics department, Guy Fontaine Medical Center, CLAD Nord de France, Jeanne de Flandre Hospital, CHRU Lille, Lille, France
  11. 11 Genetics department, GH Est, Hospices Civils de Lyon, Lyon, France
  12. 12 Medical Genetics department, Hôtel Dieu Hospital, Clermont-Ferrand, France
  13. 13 Genetics department, CHU Côte de Nacre, Caen, France
  14. 14 Medical Genetics department, CHU Ch. Nicolle, Rouen, France
  15. 15 Medical Genetics department, CHU Timone enfants, Assistance Publique des Hôpitaux de Marseille, Marseille, France
  16. 16 Department of Genetics, Reproductive biology and Histology, CHU de Rouen, Rouen, France
  17. 17 Clinical Genetics department, CHU d’Amiens, Amiens, France
  18. 18 GENDEV Team, CRNL, CNRS UMR 5292, INSERM U1028; Claude Bernard Lyon I University, Lyon, France
  19. 19 Department of Histology Embryology and Cytogenetics, Jean Verdier Hospital; Paris 13 University, Sorbonne Paris Cité, UFR SMBH Bobigny; PROTECT, INSERM, Paris Diderot University, Bondy, France
  20. 20 Division of Brain Sciences, Faculty of Medicine, Imperial College, London, UK
  21. 21 Pediatrics department, Jean Verdier Hospital, Assistance Publique des Hôpitaux de Paris, Paris 13 University, Bondy, France
  22. 22 Genetics department, CHU Robert Debré, Assistance Publique des Hôpitaux de Paris, Paris, France
  23. 23 Neuropediatrics department, Hôpital Raymond Poincaré, Assistance Publique des Hôpitaux de Paris, Garches, France
  24. 24 Medical Genetics department, Institut National d’Hygiène, Rabat, Morocco
  25. 25 Cytogenetics and Reproductive Biology department, CHU d’Amiens, Amiens, France
  26. 26 Plastic reconstructive and aesthetic surgery, Maison Blanche Hospital, Robert Debré Hospital, Reims, France
  27. 27 Pediatrics, CAMSP, Troyes, France
  28. 28 Department of Histology, Cytology, Cytogenetics, Cell Biology and Reproduction, Limoges University Hospital, Limoges, France
  29. 29 Pediatrics department, Limoges University Hospital, Limoges, France
  30. 30 Cytogenetics department, CHU Clermont-Ferrand, ERTICA, Auvergne University, Clermont-Ferrand, France
  31. 31 Nuclear Lymphocyte Biology, NIAMS, National Institutes of Health, Bethesda, Maryland, United States
  1. Correspondence to Dr Laïla Allach El Khattabi, Cytogenetics Department, Cochin Hospital, Paris 75014, France; laila.el-khattabi{at}inserm.fr

Abstract

Background The clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype–phenotype correlations to improve genetic counselling and patients’ medical care.

Methods We retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents.

Results Clinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype–phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, NDE1 and miR-484 seem to have an essential role in the neurocognitive phenotype.

Conclusion Our study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of NDE1 and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk.

  • neurodevelopmental disorder
  • 16p13.11 duplication
  • NDE1
  • MYH11
  • miR-484

https://doi.org/10.1136/jmedgenet-2018-105389

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    Footnotes

    • Contributors LAEK and EP: designed the study and collected the data. LAEK, SH and EP: analysed the data and wrote the manuscript. MDF, CV-D, AA, OB-B, MPC, LF, CF, MG, AG, AM-P, AM, MM-D, GL, MR, PE, AD-D, LDP, SCE, LS, CI, CF-F, PG and CL: performed the clinical evaluation of the patients. LAEK, SH, J-HC, JA, PC, SC-B, A-LM-B, NM, NLM, GP, ACT, AL, AN, CM, AR, CY, PV, DS, JMD, BB and EP: performed the genetic investigations. All authors revised and approved the final version.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Ethics approval French Ethical Board.

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