Structural variation of chromosomes in autism spectrum disorder

Abstract

Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.

Figure 1

Genome-wide Distribution of CNVs CNVs from the Autism Chromosome Rearrangement Database (ACRD) are plotted to the right of each chromosome (black). CNV data from the autism-specific stringent data set from the current study are shown to the left of the chromosome and is categorized as de novo (blue), overlapping/recurrent (green), CNVs overlapping with structural variation from the ACRD (yellow), and singleton CNVs (red). Note that five CNVs belong to both de novo and the recurrent categories and these are denoted by an asterisk (see Tables 2 and 3). All CNV data sets are described in Table 1 and the characteristics of the 277 CNVs depicted here are described in Table S3. The raw data from all are present in the Gene Expression Omnibus database.

Figure 2

Examples of Complexities of Structural Variants Observed in ASD Families Males are denoted by squares and females by circles. The size of each de novo or inherited event is shown below each family member. Arrows identify the proband, open shapes are unaffected, and filled have ASD diagnosis (gray denotes developmental delay but not a definitive ASD diagnosis). Diamonds indicate number of older unaffected siblings of unspecified gender. For ASD cases, probands may have multiple de novo events (A), including rearrangements overlapping genes known to be associated with ASD such as SHANK3 (B). Probands may also inherit chromosome X deletions (at PTCHD1) from female carriers (C) or have an inherited translocation in addition to an unrelated de novo deletion (D). Overlapping events in unrelated probands may be either de novo (E) or inherited (F) at the DPP6 locus. Recurrent de novo events in unrelated probands may also be either losses (G) or gains (H) at chromosome 16p11.2. Additional ASD families with CNVs at DPP6 and 16p11.2 are shown in Figures S4 and S5, respectively.