Family and twin studies strongly support a genetic predisposition for autism spectrum disorders (ASD), a neurodevelopmental disorder characterized by deficits in social interaction, communication, and repetitive behaviour [1, 2]. However, no genes capable of explaining the majority of cases have been identified to date.
While a prevalent hypothesis has been that ASD risk results from the interaction of multiple common gene variants, each with a small effect on disorder risk [1, 2], in recent years candidate gene studies, genome-wide array screenings, and exome sequencing have brought rare variants to the attention of researchers [2–6]. Rare mutations in specific genes segregating with disorders in families with ASD and/or intellectual disability (ID) have been reported, including SHANK3, NLGN3 and 4, NRXN1, and many others [7–9]. More recently, exome sequencing has uncovered variants in other genes, such as CHD8, GRIN2B, and SCN1A, in ASD individuals [10–12].
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 thus can contribute to genetic diversity and genomic evolution and influence disease risk [13, 15]. The AGP study showed that ASD patients have a significantly higher burden of rare genic CNVs, de novo and inherited, when compared to control subjects. The identified CNVs frequently overlapped genes previously implicated in ASD and ID, but also implicated novel genes like SHANK2, SYNGAP1, or DLGAP2. Interestingly, 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 .
Because CNVs frequently delete or duplicate brain expressed genes of relevance for autism, it is reasonable to assume that many are likely of pathogenic significance and altogether may explain a substantial fraction of ASD risk . The rigorous assessment of the clinical consequences of CNVs, however, requires the establishment, in large population samples, of recurrence rates in patients, clinical correlations, segregation in families, comparison of frequencies with control databases, and molecular and functional studies.
To assess the clinical significance of rare CNVs identified by the AGP study, we selected, for further characterization, de novo or inherited CNVs that were recurrent in ASD patients but absent or extremely rare in population-based control datasets. Here, we report a small recurrent CNV duplicating a segment of the annexin A1 gene (ANXA1) in ASD subjects, and its detailed characterization, including frequency in patients and controls, recurrence rates, segregation in families, and breakpoint identification. We further describe the exonic and downstream region sequencing of this gene in a second ASD sample. Annexin A1, previously known as lipocortin 1, is a 37 kDa protein belonging to the annexin protein superfamily. Annexin A1 was initially identified as a potent anti-inflammatory protein, mediating glucocorticoid (GC) actions in the host defence system . Its functional activities, however, far exceed this early discovery, and include cell migration, differentiation, and proliferation, regulation of cell death signalling, phagocytic clearance of apoptotic cells, and carcinogenesis. Annexin A1 has been detected in the brain, where it is thought to have a neuroprotective and anti-inflammatory function , and is strongly implicated in the regulation of the neuroendocrine system, in particular the hypothalamus–pituitary–adrenal (HPA) axis control by GCs .