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Original Investigation |

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

Debra D’Angelo, MS1; Sébastien Lebon, MD2; Qixuan Chen, PhD1; 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.
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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.

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Figure 1.
Distribution of IQ Measures in BP4-BP5 16p11.2 Duplication and Deletion Carriers and Intrafamilial Noncarrier Control Individuals

A-C, Box plots. Bold line indicates median; circles, outliers; dot inside the box, mean; top of each box, the 75th percentile (Q3); bottom of each box, 25th percentile (Q1); upper end of the error bar, the highest observed data value within the span from Q3 to Q3 + 1.5 times the interquartile range (IQR) (calculated as Q3 – Q1); the lower end, the lowest observed data value within the span from Q1 to Q1 – 1.5 times the IQR; shading, intellectual disability range (IQ ≤ 70); and dotted line, population mean (IQ = 100). The numbers below the graphs represent the number of duplication and deletion carriers in each group. D and E, Density plots. Increased variance is seen in the duplication group with a significant excess of low- and high-functioning duplication carriers compared with the deletion group, which was ascertained with the same method. The Full-Scale IQ (FSIQ) of probands with autism spectrum disorder (ASD) is significantly lower in duplication compared with deletion carriers.

aP < .05.

bP < .1.

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Figure 2.
Body Mass Index (BMI) and Head Circumference (HC) z Scores in Deletion and Duplication Carriers and Intrafamilial Control Individuals

Density plots depict cross-sectional data. Only data from probands were used for deletion and duplication density plots. Stratification of z scores by 6 age windows used the combined longitudinal and cross-sectional data. In the 3 youngest age windows, we compared the mean z scores (data markers; error bars indicate SEs of the estimates in linear mixed models) of deletions and duplications in each individual age window with the population mean (z score, 0). In the 3 oldest age windows where familial controls were available, we compared the mean z score for deletions and duplications in each individual age window with their familial controls. Deletion and duplication carriers demonstrate low BMI during infancy. After 2 years of age, the BMI z score of deletion carriers increases and remains low in duplication carriers. NA indicates not available.

aP < .05, carriers vs normative data, using the method of Gao et al24 for the P value calculation to account for the multiple tests across multiple age windows.

bP < .05, carriers vs controls, using the method of Gao et al24 for the P value calculation to account for the multiple tests across multiple age windows.

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