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Estimating the effect size of the 15Q11.2 BP1–BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice
  1. Aia Elise Jønch1,2,
  2. Elise Douard3,4,
  3. Clara Moreau3,4,
  4. Anke Van Dijck5,6,
  5. Marzia Passeggeri7,
  6. Frank Kooy5,6,
  7. Jacques Puechberty8,
  8. Carolyn Campbell9,
  9. Damien Sanlaville10,11,
  10. Henrietta Lefroy12,
  11. Sonia Richetin7,
  12. Aurelie Pain7,13,
  13. David Geneviève14,15,
  14. Usha Kini12,16,
  15. Cédric Le Caignec17,
  16. James Lespinasse18,
  17. Anne-Bine Skytte19,20,
  18. Bertrand Isidor17,
  19. Christiane Zweier21,
  20. Jean-Hubert Caberg22,
  21. Marie-Ange Delrue3,4,
  22. Rikke Steensbjerre Møller23,
  23. Anders Bojesen24,
  24. Helle Hjalgrim23,
  25. Charlotte Brasch-Andersen1,2,
  26. Emmanuelle Lemyre3,4,
  27. Lilian Bomme Ousager1,2,
  28. Sébastien Jacquemont3,4
  29. on behalf of 15q11.2 Working Group
    1. 1 Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
    2. 2 Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
    3. 3 Department of Pediatrics, University of Montreal, Montreal, Québec, Canada
    4. 4 Center Hospitalier Universitaire Sainte-Justine Research Center, Montreal, Québec, Canada
    5. 5 Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
    6. 6 Department of Neurology, University Hospital Antwerp, Antwerp, Belgium
    7. 7 Service of Medical Genetics, CHUV Lausanne, Lausanne, Switzerland
    8. 8 Département de Génétique Médicale, Maladies rares et Médecine personnalisée, Université Montpelier, Hôpital Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France
    9. 9 Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
    10. 10 Service de Génétique, Hospices Civils de Lyon, CHU de Lyon, Bron, France
    11. 11 Centre de Recherche en Neurosciences de Lyon, GENDEV Team, INSERM U1028, CNRS UMR5292, Université Claude Bernard Lyon, Bron, France
    12. 12 Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
    13. 13 Centre Cantonal Autisme, CHUV Lausanne, Lausanne, Switzerland
    14. 14 Département de Génétique Médicale, Hôpital Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France
    15. 15 INSERM, U1183, IRMB, Hôpital Saint Eloi, CHU de Montpellier, Montpellier, France
    16. 16 The Spires Cleft Centre, John Radcliffe Hospital, Oxford, UK
    17. 17 Service de Génétique Médical, CHU Nantes, Nantes, France
    18. 18 Service de Cytogenetique, Centre Hospitalier de Chambéry, Chambéry, France
    19. 19 Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
    20. 20 Department of Clinical epidemiology, Aarhus University, Aarhus, Denmark
    21. 21 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
    22. 22 Department of Human Genetics, CHU de Liège, Liège, Belgium
    23. 23 Danish Epilepsy Center, Filadelfia, Dianalund, Denmark
    24. 24 Department of Clinical Genetics, Sygehus Lillebalt Vejle Sygehus, Vejle, Denmark
    1. Correspondence to Dr Sébastien Jacquemont, Department of Pediatrics, University of Montreal, Montréal, QC H3T1C5, Canada; sebastien.jacquemont{at}


    Background The 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case–control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders.

    Methods We performed meta-analyses on new and previously published case–control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant.

    Results The deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias.

    Conclusions We recommend that the deletion should be classified as ‘pathogenic of mild effect size’. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting.

    • 15q11.2 copy-number variants
    • neurodevelopmental disorders
    • epilepsy
    • congenital heart disease
    • loss-of-function intolerance

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    • LBO and SJ are joint senior authors.

    • LBO and SJ contributed equally.

    • Collaborators 15q11.2 Working Group: Joris Andrieux, Angela Barnicoat, Patricia Blanchet, Sophie Blesson, Florence Niel Bütschi, Philippe M Campeau, Nora Chelloug, François-Guillaume Debray, Florence Fellmann, Alessandra Ferrarini, Richard Gibbons, Pernille Axel Gregersen, Juliane Hoyer, Ulrike Hüffmeier, Ditte Kjelgaard, Mandy Krumbiegel, Sébastien Lebon, Gaetan Lesca, Stéphanie Marignier, Sandra Mercier, Jacques Michaud, Grant Mitchell, Isabelle Mortemousque, Rikke S Møller, Mathilde Nizon, Genevieve Pierquin, Kristina Pilekær Sørensen, Sue Price, Pascal H Pujol, Vincent Ramaekers, Martine Raynaud, André Reis, Massimiliano Rossi, Pierre Sarda, Franco Stanzial, Helen Stewart, Dea Svaneby, Christian T Theil, Marianne Till, Yannis Trakadis, Dorothée Ville, Sandrine Vonwill, Andrew Wilkie, Antje Wiessner. Members of the 15q11.2 Working Group are collaborators who are listed in the supplementary file.

    • Contributors AEJ, LBO and SJ contributed to the concept, study design and wrote the manuscript. AEJ, ED, CM, MP, CBA, EL, LBO and SJ collected the data and analysed or interpreted the data. AEJ, CM, AVD, MP, RFK, JP, CC, DS, HL, SR, AP, DG, UK, CLC, JL, ABS, BI, CZ, JHC, MAD, AB and HH recruited patients and performed the clinical evaluation of patients. All authors revised and approved the final version. Collaborators, RSM on behalf of the members of the 15q11.2 Working Group provided patients for the study.

    • Funding This work was supported by grants from Odense University Hospital Free Research Fund, Grant No.15-A857 (to AEJ), the Region of Zealand and Region of Southern of Denmark Joint Research Fund, (14-001308 to AEJ), the Canadian Institute of Health Research (CIHR 159734), Ph.D. Scholarship from the Region of Southern of Denmark (to AEJ) and a PhD Scholarship from the Faculty of Health Sciences, University of Southern of Denmark (to AEJ), a Bursary Professor fellowship of the Swiss National Science Foundation (SNSF) (to SJ), a Canada Research Chair in neurodevelopmental disorders (to SJ) and a Chair from the Jeanne et Jean Louis Lévesque Foundation (to SJ).

    • Competing interests None declared.

    • Patient consent for publication Obtained.

    • Ethics approval This study was approved by the institutional review boards (IRB) of Sainte-Justine University Hospital, Montreal, Canada (MP-21-2016-946), Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland ( and the Regional Committees on Health Research Ethics for Southern Denmark (ID-20150086).

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

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

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