Detection of Copy Number Variation in New Zealand Autism Spectrum Disorder Patients

Abstract

Autism is a complex, heterogeneous genetic disorder that encompasses a broad range of phenotypes that all fall under the umbrella of Autism Spectrum Disorder (ASD). These phenotypes range from high functioning autism, formerly known as Asperger’s Syndrome, through to profound autism and can include individuals who also have intellectual disability and developmental delay. The defining clinical features of autism are impaired social interaction, communication and stereotyped behaviors. Autism also has a range of secondary symptoms including intellectual disability, epilepsy and attention deficit hyperactivity disorder (ADHD). The aim of this research was to characterize genetic variations in patients affected by autism or developmental delay by mining existing genomic copy number variation (CNV) array data supplied by LabPLUS diagnostics at Auckland Hospital. Data was generated through routine testing of patients referred for developmental delay and autism using Affymetrix 1.2M comparative genomic hybridization (CGH) microarrays and analyzed using the Chromosome Analysis Suite (ChAS) software. LabPLUS uses a specific set of diagnostic filter thresholds applied via ChAS. These were relaxed by lowering the size thresholds in this study. 199 patients were analyzed and over 1,000 copy number variations were detected. Two deletions in autism related genes were confirmed by bridging PCR and Sanger sequencing across the breakpoints which enabled base pair delineation of the breakpoint junctions. One of the deletions is likely to be pathogenic and encompasses the first exon and upstream region of the autism associated gene CNTN4. The other is a 10kb deletion of an intron in GRM8, also an autism associated gene. This research will add to the pool of information on the genetic component of autism and shows the value of characterizing mutations down to the base pair level. This research also suggests that there may be value in LabPLUS lowering their diagnostic thresholds which may result in more patients obtaining a molecular diagnosis. The hope is that this will eventually lead to treatments, prenatal diagnostics and patient group segmentation that will allow better targeting of therapies.