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A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders
  1. Flore Zufferey1,
  2. Elliott H Sherr2,
  3. Noam D Beckmann1,
  4. Ellen Hanson3,
  5. Anne M Maillard1,
  6. Loyse Hippolyte1,
  7. Aurélien Macé4,5,
  8. Carina Ferrari6,
  9. Zoltán Kutalik4,5,
  10. Joris Andrieux7,
  11. Elizabeth Aylward8,
  12. Mandy Barker9,
  13. Raphael Bernier10,
  14. Sonia Bouquillon7,
  15. Philippe Conus6,
  16. Bruno Delobel11,
  17. W Andrew Faucett12,
  18. Robin P Goin-Kochel13,
  19. Ellen Grant14,
  20. Louise Harewood15,
  21. Jill V Hunter16,
  22. Sébastien Lebon17,
  23. David H Ledbetter12,
  24. Christa Lese Martin18,
  25. Katrin Männik15,
  26. Danielle Martinet1,
  27. Pratik Mukherjee19,
  28. Melissa B Ramocki20,
  29. Sarah J Spence21,
  30. Kyle J Steinman22,
  31. Jennifer Tjernagel23,
  32. John E Spiro23,
  33. Alexandre Reymond15,
  34. Jacques S Beckmann1,4,
  35. Wendy K Chung24,
  36. Sébastien Jacquemont1,
  37. on behalf of the Simons VIP Consortium*,
  38. on behalf of the 16p11.2 European Consortium*
  1. 1Service de Génétique Médicale, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  2. 2Department of Neurology, University of California, San Francisco, California, USA
  3. 3Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  4. 4Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  5. 5Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland
  6. 6Department of Psychiatry, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  7. 7Institut de Génétique Médicale, Hopital Jeanne de Flandre, CHRU de Lille, Lille, France
  8. 8Center for Integrative Brain Research, Children's Research Institute, Seattle, Washington, USA
  9. 9Department of Child Psychiatry, SUPEA, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  10. 10Department of Psychiatry and Behavioral Science, University of Washington, Seattle, Washington, USA
  11. 11GHICL, Centre de Génétique Chromosomique, Hôpital Saint-Vincent de Paul, Lille, France
  12. 12Genomic Medicine Institute, Geisinger Clinic, Danville, Pennsylvania, USA
  13. 13Department of Pediatrics, Psychology Section, Baylor College of Medicine, Houston, Texas, USA
  14. 14Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  15. 15Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
  16. 16Department of Radiology, Baylor College of Medicine, Houston, Texas, USA
  17. 17Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  18. 18Department of Human Genetics, Emory University, Atlanta, Georgia, USA
  19. 19Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA
  20. 20Department of Pediatrics, Section of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, Texas, USA
  21. 21Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  22. 22Department of Neurology, Seattle Children's Research Institute & University of Washington, Seattle, Washington, USA
  23. 23Simons Foundation, New York, New York, USA
  24. 24Departments of Pediatrics and Medicine, Columbia University, New York, New York, USA
  25. *Members of the consortia are listed in the Supplemental Appendix.
  1. Correspondence to
    Dr Wendy Chung, Division of Molecular Genetics, Department of Pediatrics, Columbia University, Russ Berrie Pavilion, 1150 St Nicholas Avenue, Rm 620, New York, NY 10032, USA, wkc15{at}columbia.edu; Jacques S Beckmann, Service de Génétique Médicale, CHUV, Ave Pierrre Decker, 2, 1011 Lausanne, Switzerland, jacques.beckmann{at}unil.ch; Alexandre Reymond, Center for Integrative Genomics, University of Lausanne, Le Génopode, 1015 Lausanne, Switzerland, alexandre.reymond{at}unil.ch; Sébastien Jacquemont, Service de Génétique Médicale, CHUV, Ave Pierrre Decker, 2, 1011 Lausanne, Switzerland, sebastien.jacquemont{at}chuv.ch

Abstract

Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders.

Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion.

Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls.

Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations.

Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

  • Clinical genetics
  • Obesity
  • Psychiatry
  • Complex traits

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