16707
Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorder
Objectives: This work represents the latest phase of the international Autism Genome Project Consortium’s (AGP) effort to fully delineate the impact of CNV in ASD.
Methods: We assessed the impact of de novoand inherited rare CNV in a total of 2,446 ASD cases and their parents from the AGP along with 2,640 unrelated controls by applying a series of approaches to prioritize variants and key candidate ASD genes disrupted by CNVs, and to identify biological relationships and common pathways shared among those key genes. We have also integrated the latest exome sequencing data in downstream pathway studies.
Results: We confirmed an excess of genic deletions and duplications in cases over controls (1.41 fold, p=1.0x10-5) and an increase of cases carrying exonic pathogenic CNV overlapping known dominant or X-linked ASD and intellectual disability loci (odds ratio=12.62, p=2.7x10-15). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating novel ASD genes previously linked to other disorders (CHD2, HDAC4 and GDI1), as well as novel genes such as SETD5, MIR137 and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly-penetrant CNVs (p=0.017) and were also over-represented amongst cases with fragile X syndrome protein targets (p=0.02). Genes affected by de novo CNVs and/or loss-of-function single nucleotide variants converged on networks related to neuronal signalling/development, synapse function and chromatin regulation.
Conclusions: Collectively, these data inform clinical genetics interpretations, implicate specific neurobiological pathways and identify targets for therapeutic intervention.