Abstract
BackgroundValidating 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.MethodsFrom 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.ResultsThe 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.ConclusionsWe 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.
Highlights
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
Ancestry analysis (Additional file 2) clustered together the 5 Autism Genome Project (AGP) patients presenting the duplication with 3,558 European samples from the Study of Addiction: Genetics and Environment (SAGE), PopGen, and Ottawa heart institute (OHI) control populations
In a follow-up sample including 1,496 ASD patients and 410 control subjects, the annexin A1 (ANXA1) duplication was detected in 6 unrelated affected individuals and none of the controls
Summary
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. We characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study. Studies from large research groups such as the Autism Genome Project (AGP) international consortium, have highlighted the importance of highly penetrant, rare submicroscopic deletions and duplications, designated copy number variants (CNVs), in autism etiology [13,14]. These submicroscopic CNVs, ranging from 1 kb to 10 mb, occur frequently in the human genome, and can contribute to genetic diversity and genomic evolution and influence disease risk [13,15]. Target genes seemed to converge in a small number of affected pathways, with an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection, and motility as well as GTPase/Ras signalling [13]
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