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Neuroimage. 2019 Sep 5:116155. doi: 10.1016/j.neuroimage.2019.116155. [Epub ahead of print]

Developmental trajectories of neuroanatomical alterations associated with the 16p11.2 Copy Number Variations.

Author information

1
Department of Biological and Biomedical Engineering, Montreal Neurological Institute, Montreal, Quebec, Canada.
2
Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; LREN, Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
3
CHU Sainte-Justine Research Center, Université de Montréal, Montréal, QC, Canada.
4
Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; CHU Sainte-Justine Research Center, Université de Montréal, Montréal, QC, Canada.
5
Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; Centre Cantonal Autisme, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
6
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
7
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Gillberg Neuropsychiatry Centre, Göteborg, Sweden.
8
Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
9
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
10
LREN, Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
11
Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; CHU Sainte-Justine Research Center, Université de Montréal, Montréal, QC, Canada. Electronic address: Sebastien.jacquemont@umontreal.ca.
12
Service de génétique médicale, Centre Hospitalier Universitaire Vaudois, Lausanne University, Switzerland.
13
Institut de Génétique Médicale, CHRU de Lille, Hopital Jeanne de Flandre, France.
14
Service de génétique médicale, CHU de Bordeaux-GH Pellegrin, France.
15
Service de Génétique Médicale, CHU Paris - Hôpital Necker-Enfants Malades, France.
16
Service de médecine génétique, Hôpitaux Universitaires de Genève - HUG, Switzerland.
17
Service de génétique médicale, CHU d'Angers, France.
18
Institut de Génétique Médicale, Hopital Jeanne de Flandre, Lille, France.
19
Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France.
20
Genetica Medica, Dipartimento di Scienze Mediche, Università di Torino, Italy.
21
Département de génétique médicale, CHU de Marseille, Hôpital de la Timone, France.
22
Centre de génétique humaine, CHU de Liège, Belgium.
23
Service de psychiatrie, Centre hospitalier de Rouvray, Sotteville lès Rouen, France.
24
Service de génétique médicale, Centre Hospitalier Bretagne Atlantique CH Chubert- Vannes, France.
25
Service de génétique clinique, CHU de Lyon, Hospices Civils de Lyon, France.
26
Service de Génétique Médicale, CHU de Nantes, Hôtel Dieu, France.
27
Service de Génétique Humaine, CHU Sart Tilman, Liège, Belgium.
28
Service de génétique médicale, CHU de Bordeaux, Hôpital Pellegrin, France.
29
Service de Génétique et Biologie de la Reproduction, CHU de Reims, Hôpital Maison Blanche, France.
30
Department of Pediatrics, Aabenraa Hospital, Sonderjylland, Denmark.
31
Department of Clinical Genetics, Odense University hospital, Denmark.
32
Centre de génétique, Hôpital d'Enfants, CHU Dijon Bourgogne - Hôpital François Mitterrand, France.
33
Ambulatorio di Genetica Medica, Ospedali Galliera di Genova, Italy; Clinical Genetics Department, 7th Floor Borough Wing, Guy's Hospital, Guy's & St Thomas' NHS Foundation Trust, Great Maze Pond, London, SE1 9RT, UK.
34
Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, service de génétique clinique, Université Montpellier, Unité Inserm U1183, CHU Montpellier, Montpellier, France.
35
Service de Génétique, CHU de Caen, Hôpital Clémenceau, France.
36
Genetica Medica, Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Italy.
37
Service de génétique, CHU d'Angers, France.
38
Service de psychiatrie, Centre hospitalier du Rouvray, Sotteville lès Rouen, France.
39
Service de Génétique clinique, CHU Paris-GH La Pitié Salpêtrière-Charles Foix - Hôpital Pitié-Salpêtrière, France.
40
Service de Génétique Moléculaire et Génomique - Pôle biologie, CHU de Rennes, Hôpital Pontchaillou, France.
41
Centre de Génétique Moléculaire et Chromosomique, CHU Paris-GH La Pitié Salpêtrière-Charles Foix - Hôpital Pitié-Salpêtrière, France.
42
Pediatric Neurology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
43
Service de Génétique Médicale - Institut de Biologie, CHU de Nantes, France.
44
Service de Neuropédiatrie, Centre Hospitalier Régional Universitaire de Lille, France.
45
Service génétique médicale et oncogénétique, Hotel Dieu, Chambéry, France.
46
Service de Génétique Clinique, CHU Amiens Picardie, France.
47
Service de génétique clinique Guy Fontaine, Hôpital Jeanne de Flandre, CHRU de Lille, France.
48
Service de génétique clinique, CHU de Saint-Etienne - Hôpital Nord, France.
49
Laboratoire de génétique moléculaire, CHU de Bordeaux-GH Pellegrin, France.
50
Laboratoire de Cytogénétique Constitutionnelle, CHU de Lyon, Hospices Civils de Lyon, France.
51
Department of Genetics, University Medical Center Utrecht, Holland, the Netherlands.
52
Centre de Génétique humaine, CHRU de Besançon - Hôpital Saint-Jacques, France.

Abstract

Most of human genome is present in two copies (maternal and paternal). However, segments of the genome can be deleted or duplicated, and many of these genomic variations (known as Copy Number Variants) are associated with psychiatric disorders. 16p11.2 copy number variants (breakpoint 4-5) confer high risk for neurodevelopmental disorders and are associated with structural brain alterations of large effect-size. Methods used in previous studies were unable to investigate the onset of these alterations and whether they evolve with age. In this study, we aim at characterizing age-related effects of 16p11.2 copy number variants by analyzing a group with a broad age range including younger individuals. A large normative developmental dataset was used to accurately adjust for effects of age. We normalized volumes of segmented brain regions as well as volumes of each voxel defined by tensor-based morphometry. Results show that the total intracranial volumes, the global gray and white matter volumes are respectively higher and lower in deletion and duplication carriers compared to control subjects at 4.5 years of age. These differences remain stable through childhood, adolescence and adulthood until 23 years of age (range: 0.5 to 1.0 Z-score). Voxel-based results are consistent with previous findings in 16p11.2 copy number variant carriers, including increased volume in the calcarine cortex and insula in deletions, compared to controls, with an inverse effect in duplication carriers (1.0 Z-score). All large effect-size voxel-based differences are present at 4.5 years and seem to remain stable until the age of 23. Our results highlight the stability of a neuroimaging endophenotype over 2 decades during which neurodevelopmental symptoms evolve at a rapid pace.

KEYWORDS:

16p11.2 Copy number variants; Brain development; Genetics; Imaging; Neurodevelopmental disorders; Normative growth trajectories

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