Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders

Abstract

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders, including childhood autism, atypical autism, and Asperger syndrome, with an estimated prevalence of 1.0-2.5% in the general population. ASDs have a complex multifactorial etiology, with genetic causes being recognized in only 10-20% of cases. Recently, copy-number variants (CNVs) have been shown to contribute to over 10% of ASD cases. We have applied a custom-designed oligonucleotide array comparative genomic hybridization with an exonic coverage of over 1700 genes, including 221 genes known to cause autism and autism candidate genes, in a cohort of 145 patients with ASDs. The patients were classified according to ICD-10 standards and the Childhood Autism Rating Scale protocol into three groups consisting of 45 individuals with and 69 individuals without developmental delay/intellectual disability (DD/ID), and 31 patients, in whom DD/ID could not be excluded. In 12 patients, we have identified 16 copy-number changes, eight (5.5%) of which likely contribute to ASDs. In addition to known recurrent CNVs such as deletions 15q11.2 (BP1-BP2) and 3q13.31 (including DRD3 and ZBTB20), and duplications 15q13.3 and 16p13.11, our analysis revealed two novel genes clinically relevant for ASDs: ARHGAP24 (4q21.23q21.3) and SLC16A7 (12q14.1). Our results further confirm the diagnostic importance of array CGH in detection of CNVs in patients with ASDs and demonstrate that CNVs are an important cause of ASDs as a heterogeneous condition with a variety of contributory genes.

Neurodevelopmental disorders associated with dosage imbalance ofZBTB20correlate with the morbidity spectrum of ZBTB20 candidate target genes

“…This, combined with the NDD seen in patients 1 and 2 presented here, shows that ZBTB20 can be added to the growing list of shared genetic susceptibility factors for a broad range of neurodevelopmental and neuropsychiatric disorders 5 49 50. Our study further emphasises that mapping of balanced chromosomal rearrangements is a powerful approach to link specific genes to specific phenotypic traits within the growing number of microdeletion syndromes 2 5 18…”

Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes

“…32,33 However, there have been few studies assessing a large set of candidate genes thought to be causative for a complex and highly heterogeneous condition like ID. 34 Therefore, the aim of our study was to design a custom array able to identify CNVs in known ID genes/loci as well as in candidate ID genes, at single-exon resolution, which is well below the current level of detection of standard clinical CMA. Of the 36 validated de novo CNVs, 23 were intragenic, involving one or more exons within a single gene (Tables 1 and 2).…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…This suggests that ARHGAP24 could play a role in the development of dendritic spines but this has not yet been demonstrated. A de novo deletion in the locus 4q21.23q21.3, a region that only harbors the gene which codes for ARHGAP24, has been identified in ASD patients 294 .…”