Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders

Abstract

Small genomic rearrangements and copy-number variations (CNVs) involving a single gene have been associated recently with many neurocognitive phenotypes, including intellectual disability (ID), behavioral abnormalities, and autistic spectrum disorders (ASDs). Such small CNVs in the Autism susceptibility candidate 2 (AUTS2) gene have been shown to be associated with seizures, ID, and ASDs. We report four patients with small CNVs ranging in size between 133-319 kb that disrupt AUTS2. Two patients have duplications involving single exons, whereas two have deletions that removed multiple exons. All patients had developmental delay, whereas two patients had a diagnosis of ASDs. The CNVs were detected by an exon-targeted array CGH with dense oligonucleotide coverage in exons of genes known or hypothesized to be causative of multiple human phenotypes. Our report further shows that disruption of AUTS2 results in a variety of neurobehavioral phenotypes. More importantly, it demonstrates the utility of targeted exon array as a highly sensitive clinical diagnostic tool for the detection of small genomic rearrangements in the clinically relevant regions of the human genome.

Figure 1

Results of targeted exon-specific aCGH showing CNVs in four patients with developmental delay and/or ASDs. The oligonucleotide coverage in the 180k exon-targeted array clearly shows more oligos per exon as compared to the 105k genome array. The previously published reports on either translocation breakpoints (Huang et al, Sultana et al, Kalscheuer et al) or inversion breakpoints (Talkowski et al, Bakkaloglu et al ) disrupting Autism susceptibility candidate 2 (AUTS2) have been depicted. Red bars depict loss and green bars depict gain of copy number. Patients 3 and 4 with ASDs, as well as three of the previously reported patients with ASDs, have alterations in the 5′ region of the gene. Patients 1 and 2 with multiple-exon deletions have developmental delay but not ASDs.