title: Opposing brain differences in 16p11.2 deletion and duplication carriers.
abstract: Deletions and duplications of the recurrent ~600 kb chromosomal BP4-BP5 region of 16p11.2 are associated with a broad variety of neurodevelopmental outcomes including autism spectrum disorder. A clue to the pathogenesis of the copy number variant (CNV)'s effect on the brain is that the deletion is associated with a head size increase, whereas the duplication is associated with a decrease. Here we analyzed brain structure in a clinically ascertained group of human deletion (N = 25) and duplication (N = 17) carriers from the Simons Variation in Individuals Project compared with age-matched controls (N = 29 and 33, respectively). Multiple brain measures showed increased size in deletion carriers and reduced size in duplication carriers. The effects spanned global measures of intracranial volume, brain size, compartmental measures of gray matter and white matter, subcortical structures, and the cerebellum. Quantitatively, the largest effect was on the thalamus, but the collective results suggest a pervasive rather than a selective effect on the brain. Detailed analysis of cortical gray matter revealed that cortical surface area displays a strong dose-dependent effect of CNV (deletion > control > duplication), whereas average cortical thickness is less affected. These results suggest that the CNV may exert its opposing influences through mechanisms that influence early stages of embryonic brain development.
authors.affiliation: Harvard University, Department of Psychology and Center for Brain Science, Cambridge, Massachusetts 02138, Departments of Neurology and.
authors.forename: Abid Y
authors.initials: AY
authors.lastname: Qureshi
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, Ludwig Maximilians University Munich, Institute of Clinical Radiology, Munich 81377, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Mueller
authors.affiliation: Departments of Neurology and Radiology, Washington University School of Medicine in St Louis, St Louis, Missouri 63110.
authors.forename: Abraham Z
authors.initials: AZ
authors.lastname: Snyder
authors.affiliation: Departments of Radiology and Biomedical Imaging, and.
authors.forename: Pratik
authors.initials: P
authors.lastname: Mukherjee
authors.affiliation: Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Berman
authors.affiliation: Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Timothy P L
authors.initials: TP
authors.lastname: Roberts
authors.affiliation: Departments of Radiology and Biomedical Imaging, and.
authors.forename: Srikantan S
authors.initials: SS
authors.lastname: Nagarajan
authors.affiliation: Simons Foundation, New York, New York 10010, and.
authors.forename: John E
authors.initials: JE
authors.lastname: Spiro
authors.affiliation: Department of Pediatrics and Medicine, Columbia University Medical Center, New York, New York 10032.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Neurology, University of California, San Francisco, California 94158.
authors.forename: Elliott H
authors.initials: EH
authors.lastname: Sherr
authors.affiliation: Harvard University, Department of Psychology and Center for Brain Science, Cambridge, Massachusetts 02138, Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, randy_buckner@harvard.edu.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Buckner
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001921:Brain / Q000254:growth & development / Q000473:pathology*; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics / Q000473:pathology*; D002872:Chromosome Deletion; D058674:Chromosome Duplication; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D003072:Cognition Disorders / Q000235:genetics; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D012920:Social Behavior Disorders / Q000235:genetics; D055815:Young Adult
keywords: 16p11.2; ASD; CNV; copy number variation; morphometry; structural MRI