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Epigenetics
Original article
Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences
  1. Solveig Heide1,
  2. Sandra Chantot-Bastaraud1,
  3. Boris Keren2,
  4. Madeleine D Harbison3,
  5. Salah Azzi4,
  6. Sylvie Rossignol5,6,
  7. Caroline Michot7,
  8. Marilyn Lackmy-Port Lys8,
  9. Bénédicte Demeer9,
  10. Claudine Heinrichs10,
  11. Ron S Newfield3,
  12. Pierre Sarda11,
  13. Lionel Van Maldergem12,
  14. Véronique Trifard13,
  15. Eloise Giabicani14,15,16,
  16. Jean-Pierre Siffroi1,
  17. Yves Le Bouc14,15,16,
  18. Irène Netchine14,15,16,
  19. Frédéric Brioude14,15,16
  1. 1Département de Génétique, APHP, Hôpital Armand-Trousseau, UF de Génétique Chromosomique, Paris, France
  2. 2Département de Génétique, APHP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
  3. 3Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, USA
  4. 4Nuclear Dynamics ISPG, Babraham Institute, Cambridge, UK
  5. 5Service de Pédiatrie 1, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
  6. 6Laboratoire de Génétique Médicale, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
  7. 7Department of Genetics, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker Enfants Malades (AP-HP), Paris, France
  8. 8Unité de Génétique Clinique, Centre de Compétences Maladies Rares Anomalies du développement, Centre Hospitalier Universitaire Pointe-a-Pitre Abymes, Pointe-a-Pitre, France
  9. 9Service de Génétique Clinique et Oncogénétique, CLAD Nord de France, CHU Amiens-Picardie, Amiens, France
  10. 10Service d’Endocrinologie Pédiatrique, Queen Fabiola Children’s University Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium
  11. 11Service de Génétique Médicale, CHU de Montpellier, Montpellier, France
  12. 12CHU, Centre de Génétique Humaine Besançon, Université de Franche-Comté, Besançon, France
  13. 13Service de Pédiatrie, CH de La Roche sur Yon, La Roche sur Yon, France
  14. 14AP-HP, Hôpitaux Universitaires Paris Est, Hôpital des Enfants Armand Trousseau, Service d’Explorations Fonctionnelles Endocriniennes, Paris, France
  15. 15INSERM UMR_S938, Centre de Recherche Saint Antoine, Paris, France
  16. 16Sorbonne Universites, UPMC Univ Paris 06, Paris, France
  1. Correspondence to Dr Frédéric Brioude, Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau, Paris 75012, France; frederic.brioude{at}aphp.fr

Abstract

Background The 11p15 region contains two clusters of imprinted genes. Opposite genetic and epigenetic anomalies of this region result in two distinct growth disturbance syndromes: Beckwith-Wiedemann (BWS) and Silver-Russell syndromes (SRS). Cytogenetic rearrangements within this region represent less than 3% of SRS and BWS cases. Among these, 11p15 duplications were infrequently reported and interpretation of their pathogenic effects is complex.

Objectives To report cytogenetic and methylation analyses in a cohort of patients with SRS/BWS carrying 11p15 duplications and establish genotype/phenotype correlations.

Methods From a cohort of patients with SRS/BWS with an abnormal methylation profile (using ASMM-RTQ-PCR), we used SNP-arrays to identify and map the 11p15 duplications. We report 19 new patients with SRS (n=9) and BWS (n=10) carrying de novo or familial 11p15 duplications, which completely or partially span either both telomeric and centromeric domains or only one domain.

Results Large duplications involving one complete domain or both domains are associated with either SRS or BWS, depending on the parental origin of the duplication. Genotype-phenotype correlation studies of partial duplications within the telomeric domain demonstrate the prominent role of IGF2, rather than H19, in the control of growth. Furthermore, it highlights the role of CDKN1C within the centromeric domain and suggests that the expected overexpression of KCNQ1OT1 from the paternal allele (in partial paternal duplications, excluding CDKN1C) does not affect the expression of CDKN1C.

Conclusions The phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.

  • Silver Russell Syndrome
  • 11p15 Duplication
  • Beckwith-wiedemann Syndrome
  • Imprinting Disorder
  • Cnv

https://doi.org/10.1136/jmedgenet-2017-104919

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    Footnotes

    • Contributors SH collected the data and wrote the first draft. SC-B, J-PS and BK analysed and interpreted the cytogenetic analyses. MDH, SA, SR, CM, MLPL, BD, CH, RSN, PS, LVM, VT, EG and YLB recruited the patients from the different centres. FB and IN coordinated the study, recruited the patients in Trousseau hospital (Paris) and revised substantially the draft. All authors approved the final version and agreed to be accountable for all aspects of the work.

    • Competing interests None declared.

    • Patient consent Guardian consent obtained.

    • Ethics approval CCP Ile de France.

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