The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13

Abstract

A cluster of low copy repeats on the proximal long arm of chromosome 15 mediates various forms of stereotyped deletions and duplication events that cause a group of neurodevelopmental disorders that are associated with autism or autism spectrum disorders (ASD). The region is subject to genomic imprinting and the behavioral phenotypes associated with the chromosome 15q11.2-q13 disorders show a parent-of-origin specific effect that suggests that an increased copy number of maternally derived alleles contributes to autism susceptibility. Notably, nonimprinted, biallelically expressed genes within the interval also have been shown to be misexpressed in brains of patients with chromosome 15q11.2-q13 genomic disorders, indicating that they also likely play a role in the phenotypic outcome. This review provides an overview of the phenotypes of these disorders and their relationships with ASD and outlines the regional genes that may contribute to the autism susceptibility imparted by copy number variation of the region.

Fig 1

Schematic of chromosome 15q11.1-13.3 showing the position of known genes based on the UCSC genome browser. Maternally expressed transcripts highlighted in red, and paternally expressed transcripts in black. The HERC2 gene is highlighted in blue and the GOLGA8E gene is highlighted in green. (Below) The relative positions of the 5 BP clusters are shown below with sequence homology indicated by color, blue indicating regions of homology to HERC2 and green indicating regions of homology to GOLGA8E. The black and white hatching indicates a heteromorphic region near the centromere that includes a number of pseudogenes and can expand in the normal population. At least one HERC2 based repeat lies in this region. The track above the breakpoint schematic shows the density of SNP coverage for this region on the Affymetrix 6.0 whole genome array with notable gaps at the positions of the common BPs, although not all probes for detecting copy number variations are shown in the UCSC browser. The region included in Class I and Class II deletions/duplications is indicated by the black bars at the bottom with the position of the small duplication identified by Weiss et al (2008) also noted. Similarly, the region encompassed by the two most common forms of idic(15) chromosomes is indicated with solid blue line indicating a region of tetrasomy and dashed line indicating trisomy.

Figure 2

Schematic of the Genomic Rearrangements of Chromosome 15. The ideogram of chromosome 15 is shown in the middle. On the left hand side, interstitial rearrangements are shown. On the far left, PWS and AS can arise by deletion of 15q11.2-q13.1. Alternatively, this region can be duplicated, shown here as a tandem duplication of the BP1:BP3 region. These lead to trisomy of the involved segments of DNA. On the right, the two most common forms of idic(15) associated with ASD are shown, Class 3B and Class 5A. The Class 3B duplications lead to tetrasomy of the involved segments of DNA, while in the class 5A idic(15) chromosomes, there is tetrasomy for the region through BP4 and trisomy for the interval between BP4 and BP5.