Samuel J R A Chawner1, Joanne L Doherty1, Richard J L Anney1, Kevin M Antshel1, Carrie E Bearden1, Raphael Bernier1, Wendy K Chung1, Caitlin C Clements1, Sarah R Curran1, Goran Cuturilo1, Ania M Fiksinski1, Louise Gallagher1, Robin P Goin-Kochel1, Raquel E Gur1, Ellen Hanson1, Sebastien Jacquemont1, Wendy R Kates1, Leila Kushan1, Anne M Maillard1, Donna M McDonald-McGinn1, Marina Mihaljevic1, Judith S Miller1, Hayley Moss1, Milica Pejovic-Milovancevic1, Robert T Schultz1, LeeAnne Green-Snyder1, Jacob A Vorstman1, Tara L Wenger1, Jeremy Hall1, Michael J Owen1, Marianne B M van den Bree1. 1. MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom (Chawner, Doherty, Anney, Moss, Hall, Owen, van den Bree); Cardiff University Centre for Human Developmental Science, School of Psychology, Cardiff University, Cardiff, United Kingdom (Chawner); Department of Psychology, Syracuse University, Syracuse, N.Y. (Antshel); Department of Psychiatry and Behavioral Sciences and Psychology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (Bearden, Kushan); Departments of Psychiatry and Behavioral Sciences, University of Washington, Seattle (Bernier); Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, New York (Chung); Center for Autism Research, Children's Hospital of Philadelphia (Clements, Miller, Schultz); Department of Psychology, University of Pennsylvania, Philadelphia (Clements); South West London and St. George's Mental Health National Health Service Foundation Trust, London (Curran); University Children's Hospital, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Serbia (Cuturilo); Department of Psychiatry, Brain Center, University Medical Center Utrecht, the Netherlands (Fiksinski, Vorstman); Clinical Genetics Research Program, Centre for Addiction and Mental Health, and the Dalglish Family 22q Clinic for 22q11.2 Deletion Syndrome, Toronto General Hospital, University Health Network, Toronto (Fiksinski); Department of Psychiatry, Trinity College Dublin, Ireland (Gallagher); Department of Pediatrics, Baylor College of Medicine, Houston (Goin-Kochel); Lifespan Brain Institute, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia (Gur); Department of Psychiatry, Neurodevelopment and Psychosis Section, Perelman School of Medicine, University of Pennsylvania, Philadelphia (Gur); Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia (Gur, Schultz); Developmental Medicine, Children's Hospital Boston/Harvard Medical School, Boston (Hanson); Department of Pediatrics, University of Montreal (Jacquemont, Maillard); Centre de recherche, Centre Hospitalier Universitaire Sainte Justine, Montreal (Jacquemont); Department of Psychiatry and Behavioral Sciences, State University of New York at Upstate Medical University, Syracuse (Kates); Service des Troubles du Spectre de l'Autisme et Apparentés, Lausanne University Hospital, Lausanne, Switzerland (Maillard); Division of Human Genetics and Molecular Biology, Children's Hospital of Philadelphia (McDonald-McGinn); 22q and You Center, Children's Hospital of Philadelphia (McDonald-McGinn); Department of Pediatrics, University of Pennsylvania, Philadelphia (McDonald-McGinn, Schultz); Clinic for Psychiatry, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Serbia (Mihaljevic); Institute of Mental Health, Belgrade, Serbia, Faculty of Medicine, University of Belgrade, Serbia (Pejovic-Milovancevic); Simons Foundation, New York (Green-Snyder); Program in Genetics and Genome Biology, SickKids Research Institute, Toronto (Vorstman); Department of Psychiatry, Hospital for Sick Children, University of Toronto (Vorstman); Department of Pediatrics, Seattle Children's Hospital, Seattle (Wenger); and Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom (Hall, Owen, van den Bree).
Abstract
OBJECTIVE: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships. METHODS: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing. RESULTS: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits. CONCLUSIONS: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant.
OBJECTIVE: Certain copy number variants (CNVs) greatly increase the risk of autism. The authors conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships. METHODS: This international study included 547 individuals (mean age, 12.3 years [SD=4.2], 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers, and 45 22q11.2 duplication carriers), as well as 2,027 individuals (mean age, 9.1 years [SD=4.9], 86% male) with autism of heterogeneous etiology. Assessments included the Autism Diagnostic Interview-Revised and IQ testing. RESULTS: The four genetic variant groups differed in autism symptom severity, autism subdomain profile, and IQ profile. However, substantial variability was observed in phenotypic outcome in individual genetic variant groups (74%-97% of the variance, depending on the trait), whereas variability between groups was low (1%-21%, depending on the trait). CNV carriers who met autism criteria were compared with individuals with heterogeneous autism, and a range of profile differences were identified. When clinical cutoff scores were applied, 54% of individuals with one of the four CNVs who did not meet full autism diagnostic criteria had elevated levels of autistic traits. CONCLUSIONS: Many CNV carriers do not meet full diagnostic criteria for autism but nevertheless meet clinical cutoffs for autistic traits. Although profile differences between variants were observed, there is considerable variability in clinical symptoms in the same variant.
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