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JAMA Psychiatry. 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.

Collaborators (194)

Knoers VA, Martinet D, Belfiore M, Cuvellier JC, de Vries B, Delrue MA, Doco-Fenzy M, Lebel R, Leheup B, Lewis S, Mencarelli MA, Minet JC, Vincent-Delorme C, Moerman A, Mucciolo M, Ounap K, Rajcan-Separovic E, Renieri A, Sanlaville D, Faas BH, Koolen DA, Vulto-van Silfhout A, de Leeuw N, Rosenfeld JA, Filges I, Achatz E, Roetzer KM, Bonneau D, Guichet A, Lazaro L, Plessis G, Kroisel PM, Reis A, Jonveaux P, Chantot-Bastaraud S, Rauch A, Demeer B, Nordgren A, Labalme A, Ferrarini A, Ramelli GP, Guilmatre A, Joly-Helas G, Haize S, Layet V, Le Gallic S, de Fréminville B, Touraine R, Van Binsbergen E, Mathieu-Dramard M, Barth M, Blaumeiser B, Masurel A, Cailler P, Olivier-Faivre L, Malacarne M, Coutton C, Dieterich K, Satre V, Wallgren-Pettersson C, Tensgrom C, Kaksonen S, Duban-Bedu B, Holder M, Rossi M, Gaillard D, Bock D, Bednarek N, Guillin O, Bizzarri V, Flori E, Silengo M, Kooy RF, Aboura A, Beri M, Delobel B, Drunat S, Jaros Z, Kolk A, Reigo A, Zufferey F, Beckmann N, Faravelli F, Alupay H, Aaronson B, Ackerman S, Ankenman K, Anwar A, Atwell C, Bowe A, Beaudet AL, Benedetti M, Berg J, Berman J, Berry LN, Bibb AL, Blaskey L, Brennan J, Brewton CM, Buckner R, Bukshpun P, Burko J, Cali P, Cerban B, Chang Y, Cheong M, Chow V, Chu Z, Chudnovskaya D, Cornew L, Dale C, Dell J, Dempsey AG, Deschamps T, Earl R, Edgar J, Elgin J, Olson JE, Evans YL, Findlay A, Fischbach GD, Fisk C, Fregeau B, Gaetz B, Gaetz L, Garza S, Gerdts J, Glenn O, Gobuty SE, Golembski R, Greenup M, Heiken K, Hines K, Hinkley L, Jackson FI, Jenkins J 3rd, Jeremy RJ, Johnson K, Kanne SM, Kessler S, Khan SY, Ku M, Kuschner E, Laakman AL, Lam P, Lasala MW, Lee H, LaGuerre K, Levy S, Lian Cavanagh A, Llorens AV, Loftus Campe K, Luks TL, Marco EJ, Martin S, Martin AJ, Marzano G, Masson C, McGovern KE, McNally Keehn R, Miller DT, Miller FK, Moss TJ, Murray R, Nagarajan SS, Nowell KP, Owen J, Paal AM, Packer A, Page PZ, Paul BM, Peters A, Peterson D, Poduri A, Pojman NJ, Porche K, Proud MB, Qasmieh S, Ramocki MB, Reilly B, Roberts TP, Shaw D, Sinha T, Smith-Packard B, Snow Gallagher A, Swarnakar V, Thieu T, Triantafallou C, Vaughan R, Wakahiro M, Wallace A, Ward T, Wenegrat J, Wolken A.

Author information

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.

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.

Comment in

PMID:
26629640
PMCID:
PMC5894477
DOI:
10.1001/jamapsychiatry.2015.2123
[Indexed for MEDLINE]
Free PMC Article

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