25730
Cognitive and Head Circumference Differences in 16p11.2 CNV Carriers with and without Autism.
Thursday, May 11, 2017: 12:00 PM-1:40 PM
Golden Gate Ballroom (Marriott Marquis Hotel)
A. Maillard1, B. Rodriguez-Herreros2,3,4, A. Pain5,6, S. Martin5, C. Modenato5,6,7,8, C. S. Chawner9, L. Green Snyder10, E. Hanson11, R. Bernier12, R. P. Goin-Kochel13, N. Chabane14, B. Draganski7,8, J. Hall15, D. H. Skuse16, F. L. Raymond17, J. L. Doherty9, K. Mannik18, M. J. Owen9, A. Reymond19, M. van den Bree20, W. Chung21 and S. Jacquemont22, (1)Service de Génétique Médicale, Lausanne University Hospital, Pully, SWITZERLAND, (2)Lausanne University Hospital, Lausanne, Switzerland, (3)CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC, Canada, (4)Department of Pediatrics,, Université de Montréal, Montreal, QC, Canada, (5)Genetics, Lausanne University Hospital, Lausanne, Switzerland, (6)Genetics, University of Lausanne, Lausanne, Switzerland, (7)Department for Clinical Neurosciences, Lausanne University Hospital, Lausanne, Switzerland, (8)Department for Clinical Neurosciences, University of Lausanne, Lausanne, Switzerland, (9)Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Wales, United Kingdom, (10)Clinical Research Associates, Ivoryton, CT, (11)Children's Hospital Boston, Boston, MA, (12)University of Washington Autism Center, Seattle, WA, (13)Pediatrics, Baylor College of Medicine, Houston, TX, (14)INSERM U1000, Paris, France, (15)Neuroscience Mental Health Research Institute, Cardiff University, Wales, United Kingdom, (16)UCL GOS Institute of Child Health, London, UNITED KINGDOM, (17)Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, United Kingdom, (18)Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, (19)University of Lausanne, Lausanne, SWITZERLAND, (20)Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Wales, United Kingdom, (21)Simons Foundation, New York, NY, (22)University of Montreal, Montreal, QC, CANADA
Background: The phenotypic and etiologic heterogeneity of Autism Spectrum Disorder (ASD) represents a significant hurdle for research. “Genetic-first” studies have allowed focusing on groups of individuals who share the same genetic risk factor for ASD. This condition is multifactorial, and even genetic variants that carry large risk for ASD are not always associated with ASD (eg. 20% of 16p11.2 – 29.6-30.2 Mb-Hg19 – deletion and duplication carriers meet criteria for ASD). The nature of the additional factors present in these individuals with ASD is unknown.
Objectives: The aim of this study is to characterize cognitive dimensions and head circumference (HC) –a proxy for brain size – in carriers of a 16p11.2 copy number variant (CNV) with ASD and those without ASD.
Methods: A total of 265 probands carrying 16p11.2 rearrangements (174 deletion; 91 duplication) and 421 intrafamilial controls recruited from the 16p11.2 European Consortium, the Cardiff University Experiences of Children with Copy Number Variants Study and the Simons Variation in Individuals Project were included in the study. Measures included HC, ADI-R and IQ. We used linear mixed models to compare differences in phenotype between deletion and duplication carriers with and without ASD.
Results: Both the deletion and the duplication are associated with an IQ that is about 25 points lower than familial controls. ASD diagnosis in deletion carriers is associated with a 6.6-point increase in IQ mainly driven by nonverbal skills (p=0.018) and larger HC (+0.78 z-score, p=0.001) compared to deletion carriers without ASD. In contrast, duplication carriers with ASD show an additional decrease of 15 points in IQ (p= 0.002) compared to duplication carriers without ASD. Additional genetic factors underlying the ASD diagnosis in deletion carriers may be inherited since mothers have a significantly higher IQ (8 points; p=0.006) compared to mothers of carriers without ASD. The clinical profile of duplication carriers with ASD also differs significantly from that of deletion carriers with ASD. The former display more repetitive and stereotyped behaviors on the ADI-R (p=0.01).
Conclusions: The clinical differences between CNV carriers with and without ASD may inform on the nature of the additional factors present in the subgroup diagnosed with ASD. In addition, these results highlight the fact that deletion and duplication at the 16p11.2 locus are associated with two distinct underlying mechanisms predisposing to ASD.
