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).
Am J Psychiatry. 2021 Jan 1;178(1):77-86. doi: 10.1176/appi.ajp.2020.20010015.
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.
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.
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.
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.
某些拷贝数变异（CNV）极大地增加了自闭症的风险。作者进行了一项遗传学优先的研究，以调查自闭症临床表现的异质性是否由特定的基因型-表型关系所支撑。
这项国际研究包括 547 名个体（平均年龄 12.3 岁[标准差=4.2]，54%为男性），他们是基于具有与自闭症高风险相关的罕见 CNV 的遗传诊断而被确定的（82 名 16p11.2 缺失携带者、50 名 16p11.2 重复携带者、370 名 22q11.2 缺失携带者和 45 名 22q11.2 重复携带者），以及 2027 名自闭症病因异质性的个体。评估包括自闭症诊断访谈修订版和智商测试。
四个遗传变异组在自闭症症状严重程度、自闭症亚群特征和智商特征方面存在差异。然而，在个体遗传变异组中观察到表型结果存在很大的可变性（取决于特征，在 74%-97%之间），而组间的可变性较低（取决于特征，在 1%-21%之间）。符合自闭症标准的 CNV 携带者与具有异质性自闭症的个体进行了比较，并确定了一系列特征差异。当应用临床截止分数时，四个 CNV 中有 54%不符合完整自闭症诊断标准的个体具有较高水平的自闭症特征。
许多 CNV 携带者不符合自闭症的完整诊断标准，但仍符合自闭症特征的临床截止分数。尽管观察到变异之间的特征差异，但在同一变异中，临床症状存在很大的可变性。
