Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disorders
- Equal contributors
1 Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon 1649-016, Portugal
2 Center for Biodiversity, Functional & Integrative Genomics, Faculty of Sciences, University of Lisbon, Lisbon 1749-016, Portugal
3 Instituto Gulbenkian de Ciência, Oeiras 2780-156, Portugal
4 Unidade de Neurodesenvolvimento e Autismo, Centro de Desenvolvimento da Criança e Centro de Investigação e Formação Clínica, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra 3000-602, Portugal
5 Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra 3000-548, Portugal
6 Autism Research Unit, The Hospital for Sick Children and Bloorview Kids Rehab, University of Toronto, Toronto, Ontario M5G 1X8, Canada
7 Program in Neurogenetics, Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
8 The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada
9 Departments of Psychiatry, and Genetics and Genomic Sciences, Seaver Autism Center, and the Mindich Child Health & Development Institute, Mount Sinai School of Medicine, New York, NY 10029, USA
10 Institute of Psychiatric Research, Departments of Psychiatry and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
11 Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, ON M5S 1A1, Canada
Molecular Autism 2014, 5:28 doi:10.1186/2040-2392-5-28Published: 10 April 2014
Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study.
From the AGP CNV genomic screen in 2,147 ASD individuals, we selected for characterization an ANXA1 gene duplication that was absent in 4,964 population-based controls. We further screened the duplication in a follow-up sample including 1,496 patients and 410 controls, and evaluated clinical correlations and family segregation. Sequencing of exonic/downstream ANXA1 regions was performed in 490 ASD patients for identification of additional variants.
The ANXA1 duplication, overlapping the last four exons and 3’UTR region, had an overall prevalence of 11/3,643 (0.30%) in unrelated ASD patients but was not identified in 5,374 controls. Duplication carriers presented no distinctive clinical phenotype. Family analysis showed neuropsychiatric deficits and ASD traits in multiple relatives carrying the duplication, suggestive of a complex genetic inheritance. Sequencing of exonic regions and the 3’UTR identified 11 novel changes, but no obvious variants with clinical significance.
We provide multilevel evidence for a role of ANXA1 in ASD etiology. Given its important role as mediator of glucocorticoid function in a wide variety of brain processes, including neuroprotection, apoptosis, and control of the neuroendocrine system, the results add ANXA1 to the growing list of rare candidate genetic etiological factors for ASD.