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Original Investigation
January 2016

Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

Debra D’Angelo, MS1; Sébastien Lebon, MD2; Qixuan Chen, PhD1; et al Sandra Martin-Brevet, MS3; LeeAnne Green Snyder, PhD4; Loyse Hippolyte, PhD3; Ellen Hanson, PhD5; Anne M. Maillard, PhD3; W. Andrew Faucett, MS6; Aurélien Macé, MS3,7; Aurélie Pain, MS3; Raphael Bernier, PhD8; Samuel J. R. A. Chawner, MA9; Albert David, MD10; Joris Andrieux, MD, PhD11; Elizabeth Aylward, MD12; Genevieve Baujat, MD13,14,15; Ines Caldeira, MD3; Philippe Conus, MD16; Carrina Ferrari, MS16; Francesca Forzano, MD17; Marion Gérard, MD18; Robin P. Goin-Kochel, PhD19; Ellen Grant, MD20; Jill V. Hunter, MD21; Bertrand Isidor, MD, PhD10; Aurélia Jacquette, MD22,23,24; Aia E. Jønch, MD3; Boris Keren, MD25; Didier Lacombe, MD10,26; Cédric Le Caignec, MD, PhD10; Christa Lese Martin, PhD27; Katrin Männik, PhD28,29; Andres Metspalu, PhD29,30; Cyril Mignot, MD20; Pratik Mukherjee, MD31; Michael J. Owen, PhD9; Marzia Passeggeri, MD3; Caroline Rooryck-Thambo, MD26,32; Jill A. Rosenfeld, PhD33; Sarah J. Spence, MD, PhD34; Kyle J. Steinman, MD35; Jennifer Tjernagel, MS4; Mieke Van Haelst, MD36; Yiping Shen, PhD37; Bogdan Draganski, MD38; Elliott H. Sherr, MD, PhD39; David H. Ledbetter, PhD27; Marianne B. M. van den Bree, PhD9; Jacques S. Beckmann, PhD3,7; John E. Spiro, PhD40; Alexandre Reymond, PhD28; Sébastien Jacquemont, MD3,41,42; Wendy K. Chung, MD, PhD43,44; for the Cardiff University Experiences of Children With Copy Number Variants (ECHO) Study, the 16p11.2 European Consortium, and the Simons Variation in Individuals Project (VIP) Consortium
Author Affiliations
  • 1Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York
  • 2Pediatric Neurology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland
  • 3Department of Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
  • 4Clinical Research Associates, New York, New York
  • 5Department of Psychiatry, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 6Genomic Medicine Institute, Geisinger Clinic, Danville, Pennsylvania
  • 7Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland
  • 8Department of Psychiatry and Behavioral Science, University of Washington, Seattle
  • 9Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, Wales
  • 10Service de Génétique Médicale, Faculté de Médecine, Centre Hospitalier Universitaire (CHU) Nantes, Institut National de la Santé et de la Recherche Medicale (INSERM) Unités Mixtes de Recherche 957, Nantes, France
  • 11Institut de Génétique Médicale, Hospital Jeanne de Flandre, Centre Hospitalier Régional Universitaire (CHRU) de Lille, Lille, France
  • 12Center for Integrative Brain Research, Children’s Research Institute, Seattle, Washington
  • 13Département de Génétique, Hôpital Necker–Enfants Malades, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France
  • 14INSERM U1163, Hôpital Necker–Enfants Malades, Paris, France
  • 15Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France
  • 16Department of Psychiatry, Cery Hospital, CHU Vaudois and University of Lausanne, Lausanne, Switzerland
  • 17Division of Medical Genetics, Galliera Hospital, Genova, Italy
  • 18Departement de Génétique, AP-HP, Hôpital Robert Debré, Université Paris VII-Paris Diderot, Paris, France
  • 19Section of Psychology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
  • 20Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 21Department of Radiology, Baylor College of Medicine, Houston, Texas
  • 22Département de Génétique et de Cytogénétique, Unité fonctionnelle de Génétique Clinique, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France
  • 23Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France
  • 24Groupe de Recherche Clinique, Déficience Intellectuelle et Autisme, Université Pierre-et-Marie-Curie, Paris, France
  • 25Department of Genetics and Cytogenetics, Groupe Hospitalier Pitié Salpêtrière, AP-HP, Paris, France
  • 26Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
  • 27Autism and Developmental Medicine Institute, Geisinger Health System, Danville, Pennsylvania
  • 28Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
  • 29Estonian Genome Center, University of Tartu, Tartu, Estonia
  • 30Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
  • 31Department of Radiology and Biomedical Imaging, University of California, San Francisco
  • 32Laboratoire Maladies Rares: Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France
  • 33Signature Genomic Laboratories, LLC, PerkinElmer, Inc, Spokane,
  • 34Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 35Department of Neurology, Seattle Children’s Research Institute and University of Washington, Seattle
  • 36Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands
  • 37Genetic Diagnostic Laboratory, Department of Laboratory Medicine, Children’s Hospital, Boston, Massachusetts
  • 38Laboratoire de Recherche en Neuroimagerie, Department for Clinical Neurosciences, Centre Hospitalo-Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
  • 39Department of Neurology, University of California, San Francisco
  • 40Simons Foundation, New York, New York
  • 41CHU Sainte-Justine Research Center, Montreal, Canada
  • 42Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada
  • 43Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, New York
  • 44Department of Medicine, Columbia University, New York, New York
JAMA Psychiatry. 2016;73(1):20-30. doi:10.1001/jamapsychiatry.2015.2123

Importance  The 16p11.2 BP4-BP5 duplication is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and comorbidities such as decreased body mass index (BMI).

Objectives  To characterize the effects of the 16p11.2 duplication on cognitive, behavioral, medical, and anthropometric traits and to understand the specificity of these effects by systematically comparing results in duplication carriers and reciprocal deletion carriers, who are also at risk for ASD.

Design, Setting, and Participants  This international cohort study of 1006 study participants compared 270 duplication carriers with their 102 intrafamilial control individuals, 390 reciprocal deletion carriers, and 244 deletion controls from European and North American cohorts. Data were collected from August 1, 2010, to May 31, 2015 and analyzed from January 1 to August 14, 2015. Linear mixed models were used to estimate the effect of the duplication and deletion on clinical traits by comparison with noncarrier relatives.

Main Outcomes and Measures  Findings on the Full-Scale IQ (FSIQ), Nonverbal IQ, and Verbal IQ; the presence of ASD or other DSM-IV diagnoses; BMI; head circumference; and medical data.

Results  Among the 1006 study participants, the duplication was associated with a mean FSIQ score that was lower by 26.3 points between proband carriers and noncarrier relatives and a lower mean FSIQ score (16.2-11.4 points) in nonproband carriers. The mean overall effect of the deletion was similar (–22.1 points; P < .001). However, broad variation in FSIQ was found, with a 19.4- and 2.0-fold increase in the proportion of FSIQ scores that were very low (≤40) and higher than the mean (>100) compared with the deletion group (P < .001). Parental FSIQ predicted part of this variation (approximately 36.0% in hereditary probands). Although the frequency of ASD was similar in deletion and duplication proband carriers (16.0% and 20.0%, respectively), the FSIQ was significantly lower (by 26.3 points) in the duplication probands with ASD. There also were lower head circumference and BMI measurements among duplication carriers, which is consistent with the findings of previous studies.

Conclusions and Relevance  The mean effect of the duplication on cognition is similar to that of the reciprocal deletion, but the variance in the duplication is significantly higher, with severe and mild subgroups not observed with the deletion. These results suggest that additional genetic and familial factors contribute to this variability. Additional studies will be necessary to characterize the predictors of cognitive deficits.