. 2016 Jan;73(1):20-30.

doi: 10.1001/jamapsychiatry.2015.2123.

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

Debra D'Angelo¹, Sébastien Lebon², Qixuan Chen¹, Sandra Martin-Brevet³, LeeAnne Green Snyder⁴, Loyse Hippolyte³, Ellen Hanson⁵, Anne M Maillard³, W Andrew Faucett⁶, Aurélien Macé⁷, Aurélie Pain³, Raphael Bernier⁸, Samuel J R A Chawner⁹, Albert David¹⁰, Joris Andrieux¹¹, Elizabeth Aylward¹², Genevieve Baujat¹³, Ines Caldeira³, Philippe Conus¹⁴, Carrina Ferrari¹⁴, Francesca Forzano¹⁵, Marion Gérard¹⁶, Robin P Goin-Kochel¹⁷, Ellen Grant¹⁸, Jill V Hunter¹⁹, Bertrand Isidor¹⁰, Aurélia Jacquette²⁰, Aia E Jønch³, Boris Keren²¹, Didier Lacombe²², Cédric Le Caignec¹⁰, Christa Lese Martin²³, Katrin Männik²⁴, Andres Metspalu²⁵, Cyril Mignot¹⁸, Pratik Mukherjee²⁶, Michael J Owen⁹, Marzia Passeggeri³, Caroline Rooryck-Thambo²⁷, Jill A Rosenfeld²⁸, Sarah J Spence²⁹, Kyle J Steinman³⁰, Jennifer Tjernagel⁴, Mieke Van Haelst³¹, Yiping Shen³², Bogdan Draganski³³, Elliott H Sherr³⁴, David H Ledbetter²³, Marianne B M van den Bree⁹, Jacques S Beckmann⁷, John E Spiro³⁵, Alexandre Reymond³⁶, Sébastien Jacquemont³⁷, Wendy K Chung³⁸; Cardiff University Experiences of Children With Copy Number Variants (ECHO) Study; 16p11.2 European Consortium; Simons Variation in Individuals Project (VIP) Consortium

Collaborators, Affiliations

Collaborators

V A M Knoers, Danielle Martinet, Marco Belfiore, Jean-Christophe Cuvellier, Bert de Vries, Marie-Ange Delrue, Martine Doco-Fenzy, Robert Lebel, Bruno Leheup, Suzanne Lewis, Maria Antonietta Mencarelli, Jean-Claude Minet, Catherine Vincent-Delorme, Alexandre Moerman, Mafalda Mucciolo, Katrin Ounap, Evica Rajcan-Separovic, Alessandra Renieri, Damien Sanlaville, Brigitte H Faas, David A Koolen, Anneke Vulto-van Silfhout, Nicole de Leeuw, Jill A Rosenfeld, Isabel Filges, Eveline Achatz, Katharina M Roetzer, Dominique Bonneau, Agnès Guichet, Leila Lazaro, Ghislaine Plessis, Peter M Kroisel, Andre Reis, Philippe Jonveaux, Sandrine Chantot-Bastaraud, Anita Rauch, Bénédicte Demeer, Ann Nordgren, Audrey Labalme, Alessandra Ferrarini, Gian Paolo Ramelli, Audrey Guilmatre, Géraldine Joly-Helas, Shanon Haize, Valérie Layet, Solenn Le Gallic, Bénédicte de Fréminville, Renaud Touraine, Ellen Van Binsbergen, Michèle Mathieu-Dramard, Magalie Barth, Bettina Blaumeiser, Alice Masurel, Patrick Cailler, Laurence Olivier-Faivre, Michela Malacarne, Charles Coutton, Klaus Dieterich, Véronique Satre, Carina Wallgren-Pettersson, Carola Tensgrom, Satu Kaksonen, Bénédicte Duban-Bedu, Murielle Holder, Massimiliano Rossi, Dominique Gaillard, D Bock, Nathalie Bednarek, Olivier Guillin, Veronica Bizzarri, Elisabeth Flori, Margherita Silengo, R Frank Kooy, Azzedine Aboura, Mylène Beri, Bruno Delobel, Séverine Drunat, Zdenek Jaros, Anneli Kolk, Anu Reigo, Flore Zufferey, Noam Beckmann, Francesca Faravelli, Hanalore Alupay, Benjamin Aaronson, Sean Ackerman, Katy Ankenman, Ayesha Anwar, Constance Atwell, Alexandra Bowe, Arthur L Beaudet, Marta Benedetti, Jessica Berg, Jeffrey Berman, Leandra N Berry, Audrey L Bibb, Lisa Blaskey, Jonathan Brennan, Christie M Brewton, Randy Buckner, Polina Bukshpun, Jordan Burko, Phil Cali, Bettina Cerban, Yishin Chang, Maxwell Cheong, Vivian Chow, Zili Chu, Darina Chudnovskaya, Lauren Cornew, Corby Dale, John Dell, Allison G Dempsey, Trent Deschamps, Rachel Earl, James Edgar, Jenna Elgin, Jennifer Endre Olson, Yolanda L Evans, Anne Findlay, Gerald D Fischbach, Charlie Fisk, Brieana Fregeau, Bill Gaetz, Leah Gaetz, Silvia Garza, Jennifer Gerdts, Orit Glenn, Sarah E Gobuty, Rachel Golembski, Marion Greenup, Kory Heiken, Katherine Hines, Leighton Hinkley, Frank I Jackson, Julian Jenkins 3rd, Rita J Jeremy, Kelly Johnson, Stephen M Kanne, Sudha Kessler, Sarah Y Khan, Matthew Ku, Emily Kuschner, Anna L Laakman, Peter Lam, Morgan W Lasala, Hana Lee, Kevin LaGuerre, Susan Levy, Alyss Lian Cavanagh, Ashlie V Llorens, Katherine Loftus Campe, Tracy L Luks, Elysa J Marco, Stephen Martin, Alastair J Martin, Gabriela Marzano, Christina Masson, Kathleen E McGovern, Rebecca McNally Keehn, David T Miller, Fiona K Miller, Timothy J Moss, Rebecca Murray, Srikantan S Nagarajan, Kerri P Nowell, Julia Owen, Andrea M Paal, Alan Packer, Patricia Z Page, Brianna M Paul, Alana Peters, Danica Peterson, Annapurna Poduri, Nicholas J Pojman, Ken Porche, Monica B Proud, Saba Qasmieh, Melissa B Ramocki, Beau Reilly, Timothy P L Roberts, Dennis Shaw, Tuhin Sinha, Bethanny Smith-Packard, Anne Snow Gallagher, Vivek Swarnakar, Tony Thieu, Christina Triantafallou, Roger Vaughan, Mari Wakahiro, Arianne Wallace, Tracey Ward, Julia Wenegrat, Anne Wolken

Affiliations

¹ Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York.
² Pediatric Neurology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
³ Department of Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁴ Clinical Research Associates, New York, New York.
⁵ Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
⁶ Genomic Medicine Institute, Geisinger Clinic, Danville, Pennsylvania.
⁷ Department of Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland7Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
⁸ Department of Psychiatry and Behavioral Science, University of Washington, Seattle.
⁹ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, Wales.
¹⁰ Service 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.
¹¹ Institut de Génétique Médicale, Hospital Jeanne de Flandre, Centre Hospitalier Régional Universitaire (CHRU) de Lille, Lille, France.
¹² Center for Integrative Brain Research, Children's Research Institute, Seattle, Washington.
¹³ Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France 14INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France15Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité, Paris.
¹⁴ Department of Psychiatry, Cery Hospital, CHU Vaudois and University of Lausanne, Lausanne, Switzerland.
¹⁵ Division of Medical Genetics, Galliera Hospital, Genova, Italy.
¹⁶ Departement de Génétique, AP-HP, Hôpital Robert Debré, Université Paris VII-Paris Diderot, Paris, France.
¹⁷ Section of Psychology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
¹⁸ Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
¹⁹ Department of Radiology, Baylor College of Medicine, Houston, Texas.
²⁰ Département de Génétique et de Cytogénétique, Unité fonctionnelle de Génétique Clinique, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France23Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France24Groupe de Recherche Clinique, Déficie.
²¹ Department of Genetics and Cytogenetics, Groupe Hospitalier Pitié Salpêtrière, AP-HP, Paris, France.
²² Service 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, France26Service de Génétique Médicale, CHU de Bor.
²³ Autism and Developmental Medicine Institute, Geisinger Health System, Danville, Pennsylvania.
²⁴ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland29Estonian Genome Center, University of Tartu, Tartu, Estonia.
²⁵ Estonian Genome Center, University of Tartu, Tartu, Estonia30Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
²⁶ Department of Radiology and Biomedical Imaging, University of California, San Francisco.
²⁷ Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France32Laboratoire Maladies Rares: Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France.
²⁸ Signature Genomic Laboratories, LLC, PerkinElmer, Inc, Spokane.
²⁹ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
³⁰ Department of Neurology, Seattle Children's Research Institute and University of Washington, Seattle.
³¹ Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands.
³² Genetic Diagnostic Laboratory, Department of Laboratory Medicine, Children's Hospital, Boston, Massachusetts.
³³ Laboratoire de Recherche en Neuroimagerie, Department for Clinical Neurosciences, Centre Hospitalo-Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
³⁴ Department of Neurology, University of California, San Francisco.
³⁵ Simons Foundation, New York, New York.
³⁶ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
³⁷ Department of Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland41CHU Sainte-Justine Research Center, Montreal, Canada42Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
³⁸ Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, New York44Department of Medicine, Columbia University, New York, New York.

PMID: 26629640
PMCID: PMC5894477
DOI: 10.1001/jamapsychiatry.2015.2123

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

Debra D'Angelo et al. JAMA Psychiatry. 2016 Jan.

. 2016 Jan;73(1):20-30.

doi: 10.1001/jamapsychiatry.2015.2123.

Authors

Collaborators

V A M Knoers, Danielle Martinet, Marco Belfiore, Jean-Christophe Cuvellier, Bert de Vries, Marie-Ange Delrue, Martine Doco-Fenzy, Robert Lebel, Bruno Leheup, Suzanne Lewis, Maria Antonietta Mencarelli, Jean-Claude Minet, Catherine Vincent-Delorme, Alexandre Moerman, Mafalda Mucciolo, Katrin Ounap, Evica Rajcan-Separovic, Alessandra Renieri, Damien Sanlaville, Brigitte H Faas, David A Koolen, Anneke Vulto-van Silfhout, Nicole de Leeuw, Jill A Rosenfeld, Isabel Filges, Eveline Achatz, Katharina M Roetzer, Dominique Bonneau, Agnès Guichet, Leila Lazaro, Ghislaine Plessis, Peter M Kroisel, Andre Reis, Philippe Jonveaux, Sandrine Chantot-Bastaraud, Anita Rauch, Bénédicte Demeer, Ann Nordgren, Audrey Labalme, Alessandra Ferrarini, Gian Paolo Ramelli, Audrey Guilmatre, Géraldine Joly-Helas, Shanon Haize, Valérie Layet, Solenn Le Gallic, Bénédicte de Fréminville, Renaud Touraine, Ellen Van Binsbergen, Michèle Mathieu-Dramard, Magalie Barth, Bettina Blaumeiser, Alice Masurel, Patrick Cailler, Laurence Olivier-Faivre, Michela Malacarne, Charles Coutton, Klaus Dieterich, Véronique Satre, Carina Wallgren-Pettersson, Carola Tensgrom, Satu Kaksonen, Bénédicte Duban-Bedu, Murielle Holder, Massimiliano Rossi, Dominique Gaillard, D Bock, Nathalie Bednarek, Olivier Guillin, Veronica Bizzarri, Elisabeth Flori, Margherita Silengo, R Frank Kooy, Azzedine Aboura, Mylène Beri, Bruno Delobel, Séverine Drunat, Zdenek Jaros, Anneli Kolk, Anu Reigo, Flore Zufferey, Noam Beckmann, Francesca Faravelli, Hanalore Alupay, Benjamin Aaronson, Sean Ackerman, Katy Ankenman, Ayesha Anwar, Constance Atwell, Alexandra Bowe, Arthur L Beaudet, Marta Benedetti, Jessica Berg, Jeffrey Berman, Leandra N Berry, Audrey L Bibb, Lisa Blaskey, Jonathan Brennan, Christie M Brewton, Randy Buckner, Polina Bukshpun, Jordan Burko, Phil Cali, Bettina Cerban, Yishin Chang, Maxwell Cheong, Vivian Chow, Zili Chu, Darina Chudnovskaya, Lauren Cornew, Corby Dale, John Dell, Allison G Dempsey, Trent Deschamps, Rachel Earl, James Edgar, Jenna Elgin, Jennifer Endre Olson, Yolanda L Evans, Anne Findlay, Gerald D Fischbach, Charlie Fisk, Brieana Fregeau, Bill Gaetz, Leah Gaetz, Silvia Garza, Jennifer Gerdts, Orit Glenn, Sarah E Gobuty, Rachel Golembski, Marion Greenup, Kory Heiken, Katherine Hines, Leighton Hinkley, Frank I Jackson, Julian Jenkins 3rd, Rita J Jeremy, Kelly Johnson, Stephen M Kanne, Sudha Kessler, Sarah Y Khan, Matthew Ku, Emily Kuschner, Anna L Laakman, Peter Lam, Morgan W Lasala, Hana Lee, Kevin LaGuerre, Susan Levy, Alyss Lian Cavanagh, Ashlie V Llorens, Katherine Loftus Campe, Tracy L Luks, Elysa J Marco, Stephen Martin, Alastair J Martin, Gabriela Marzano, Christina Masson, Kathleen E McGovern, Rebecca McNally Keehn, David T Miller, Fiona K Miller, Timothy J Moss, Rebecca Murray, Srikantan S Nagarajan, Kerri P Nowell, Julia Owen, Andrea M Paal, Alan Packer, Patricia Z Page, Brianna M Paul, Alana Peters, Danica Peterson, Annapurna Poduri, Nicholas J Pojman, Ken Porche, Monica B Proud, Saba Qasmieh, Melissa B Ramocki, Beau Reilly, Timothy P L Roberts, Dennis Shaw, Tuhin Sinha, Bethanny Smith-Packard, Anne Snow Gallagher, Vivek Swarnakar, Tony Thieu, Christina Triantafallou, Roger Vaughan, Mari Wakahiro, Arianne Wallace, Tracey Ward, Julia Wenegrat, Anne Wolken

Affiliations

¹ Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York.
² Pediatric Neurology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
³ Department of Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁴ Clinical Research Associates, New York, New York.
⁵ Department of Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
⁶ Genomic Medicine Institute, Geisinger Clinic, Danville, Pennsylvania.
⁷ Department of Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland7Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
⁸ Department of Psychiatry and Behavioral Science, University of Washington, Seattle.
⁹ Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, Wales.
¹⁰ Service 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.
¹¹ Institut de Génétique Médicale, Hospital Jeanne de Flandre, Centre Hospitalier Régional Universitaire (CHRU) de Lille, Lille, France.
¹² Center for Integrative Brain Research, Children's Research Institute, Seattle, Washington.
¹³ Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France 14INSERM U1163, Hôpital Necker-Enfants Malades, Paris, France15Institut Imagine, Université Paris Descartes-Sorbonne Paris Cité, Paris.
¹⁴ Department of Psychiatry, Cery Hospital, CHU Vaudois and University of Lausanne, Lausanne, Switzerland.
¹⁵ Division of Medical Genetics, Galliera Hospital, Genova, Italy.
¹⁶ Departement de Génétique, AP-HP, Hôpital Robert Debré, Université Paris VII-Paris Diderot, Paris, France.
¹⁷ Section of Psychology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
¹⁸ Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
¹⁹ Department of Radiology, Baylor College of Medicine, Houston, Texas.
²⁰ Département de Génétique et de Cytogénétique, Unité fonctionnelle de Génétique Clinique, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France23Centre de Référence Déficiences Intellectuelles de Causes Rares, Paris, France24Groupe de Recherche Clinique, Déficie.
²¹ Department of Genetics and Cytogenetics, Groupe Hospitalier Pitié Salpêtrière, AP-HP, Paris, France.
²² Service 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, France26Service de Génétique Médicale, CHU de Bor.
²³ Autism and Developmental Medicine Institute, Geisinger Health System, Danville, Pennsylvania.
²⁴ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland29Estonian Genome Center, University of Tartu, Tartu, Estonia.
²⁵ Estonian Genome Center, University of Tartu, Tartu, Estonia30Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
²⁶ Department of Radiology and Biomedical Imaging, University of California, San Francisco.
²⁷ Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France32Laboratoire Maladies Rares: Génétique et Métabolisme, Université de Bordeaux, Bordeaux, France.
²⁸ Signature Genomic Laboratories, LLC, PerkinElmer, Inc, Spokane.
²⁹ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
³⁰ Department of Neurology, Seattle Children's Research Institute and University of Washington, Seattle.
³¹ Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands.
³² Genetic Diagnostic Laboratory, Department of Laboratory Medicine, Children's Hospital, Boston, Massachusetts.
³³ Laboratoire de Recherche en Neuroimagerie, Department for Clinical Neurosciences, Centre Hospitalo-Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
³⁴ Department of Neurology, University of California, San Francisco.
³⁵ Simons Foundation, New York, New York.
³⁶ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
³⁷ Department of Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland41CHU Sainte-Justine Research Center, Montreal, Canada42Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
³⁸ Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, New York44Department of Medicine, Columbia University, New York, New York.

PMID: 26629640
PMCID: PMC5894477
DOI: 10.1001/jamapsychiatry.2015.2123

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

**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. ^a P < .05. ^b P < .1.

**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. ^a P < .05, carriers vs normative data, using themethod of Gao et al for the P value calculation to account for the multiple tests across multiple age windows. ^b P < .05, carriers vs controls, using the method of Gao et al for the P value calculation to account for the multiple tests across multiple age windows.

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Comment in

Following the Trail From Genotype to Phenotypes.
Lord C, Veenstra-VanderWeele J. Lord C, et al. JAMA Psychiatry. 2016 Jan;73(1):7-8. doi: 10.1001/jamapsychiatry.2015.2344. JAMA Psychiatry. 2016. PMID: 26630619 No abstract available.

References

1. Weiss LA, Shen Y, Korn JM, et al. Autism Consortium. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008;358(7):667–675. - PubMed
1. Kumar RA, Kara Mohamed S, Sudi J, et al. Recurrent 16p11.2microdeletions in autism. Hum Mol Genet. 2008;17(4):628–638. - PubMed
1. Marshall CR, Noor A, Vincent JB, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82(2):477–488. - PMC - PubMed
1. McCarthy SE, Makarov V, Kirov G, et al. Wellcome Trust Case Control Consortium. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009;41(11):1223–1227. - PMC - PubMed
1. Zufferey F, Sherr EH, Beckmann ND, et al. Simons VIP Consortium: 16p11.2 European Consortium. A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. J Med Genet. 2012;49(10):660–668. - PMC - PubMed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical