Genetic diagnosis of autism spectrum disorders: the opportunity and challenge in the genomics era

Abstract

A genetic etiology for autism spectrum disorders (ASDs) was first suggested from twin studies reported in the 1970s. The identification of gene mutations in syndromic ASDs provided evidence to support a genetic cause of ASDs. More recently, genome-wide copy number variant and sequence analyses have uncovered a list of rare and highly penetrant copy number variants (CNVs) or single nucleotide variants (SNVs) associated with ASDs, which has strengthened the claim of a genetic etiology for ASDs. Findings from research studies in the genetics of ASD now support an important role for molecular diagnostics in the clinical genetics evaluation of ASDs. Various molecular diagnostic assays including single gene tests, targeted multiple gene panels and copy number analysis should all be considered in the clinical genetics evaluation of ASDs. Whole exome sequencing could also be considered in selected clinical cases. However, the challenge that remains is to determine the causal role of genetic variants identified through molecular testing. Variable expressivity, pleiotropic effects and incomplete penetrance associated with CNVs and SNVs also present significant challenges for genetic counseling and prenatal diagnosis.

Keywords: Autism spectrum disorders; array comparative genomic hybridization; copy number variation; prenatal diagnosis; single nucleotide variant; whole exome sequencing; whole genome sequencing.

Figure 1

The flowchart for clinical genetics evaluation of ASDs. *Proceeding with WES should be dictated by clinical judgment at this stage.

Figure 2

Comparison of different array CGH platforms. (A) Array results for chromosome 8 shows an intragenic deletion of exons 4–14 in the VPS13B gene which is associated with Cohen syndrome. The log2 ratio suggests the deletion is homozygous. (B) The SNP data plot reveals an AOH block (high-lighted rectangle) corresponding to the region on 8q that includes the VPS13B gene. Together, these results confirm a homozygous intragenic deletion. (C) Comparison of the probe distribution within the VPS13B gene between the exon-targeted BCM array and two commercial SNP arrays (Illumina 1M and Affy CytoscanHD). Note that the oligonucleotide probes (red dots [gray dots in print version]) on the BCM array are strategically selected for their location within the exons (hatch marks at bottom of figure and included in the boxes) whereas the SNP probes (black dots) predominate outside the exons and thus are unable to detect single exonic CNVs.

Figure 3

The workflow of WES and WGS in clinical diagnostic applications.