Reduced transcript expression of genes affected by inherited and de novo CNVs in autism

Abstract

Individuals with autism are more likely to carry rare inherited and de novo copy number variants (CNVs). However, further research is needed to establish which CNVs are causal and the mechanisms by which these CNVs influence autism. We examined genomic DNA of children with autism (N¼41) and healthy controls (N¼367) for rare CNVs using a high-resolution array comparative genomic hybridization platform. We show that individuals with autism are more likely to harbor rare CNVs as small as B10 kb, a threshold not previously detectable, and that CNVs in cases disproportionately affect genes involved in transcription, nervous system development, and receptor activity. We also show that a subset of genes that have known or suspected allele-specific or imprinting effects and are within rare-case CNVs may undergo loss of transcript expression. In particular, expression of CNTNAP2 and ZNF214 are decreased in probands compared with their unaffected transmitting parents. Furthermore, expression of PRODH and ARID1B, two genes affected by de novo CNVs, are decreased in probands compared with controls. These results suggest that for some genes affected by CNVs in autism, reduced transcript expression may be a mechanism of pathogenesis during neurodevelopment.

Recurrent Transmission of a 17q12 Microdeletion and a Variable Clinical Spectrum

“…There were no additional CNV calls in any of the family members, which strongly suggests a modifier of unknown origin as previously reported in thrombocytopenia-absent radius syndrome (OMIM 274000) [Klopocki et al, 2007]. There may be a smaller CNV occurring elsewhere in the genome, below the resolution detected by Affymetrix arrays, and conferring a transcription-related, neurodevelopmental or receptor function that exacerbates the effect of the 17q12 deletion in the offspring [Nord et al, 2011]. Alternatively, there may be a relatively common variant or polymorphism which acts as trigger.…”

Shining a light on CNTNAP2: complex functions to complex disorders

“…20 Finally, an autistic patient was identified carrying a deletion of an putative upstream promoter region, which resulted in reduced expression levels. 21 Thus, although these deletions do not interrupt the protein product, they may affect regulatory elements to produce altered functional levels of CNTNAP2.…”

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

“…More recently, we have found that loss of GluD1 produces molecular phenotypes relevant to autism and developmental delay, including impaired dendritic spine pruning and switch in N-methyl-D-aspartate (NMDA) receptor GluN2B to the GluN2A subunit in the hippocampus and prefrontal cortex (Grossman et al, 2006;Penzes et al, 2011;Swanger et al, 2011;Gupta et al, 2015). Indeed, singlenucleotide polymorphism and copy-number variation studies have identified the GRID1 gene, which codes for GluD1, as a susceptibility gene for autism, schizophrenia, bipolar disorder, and major depression (Fallin et al, 2005;Glessner et al, 2009;Smith et al, 2009;Greenwood et al, 2011;Nord et al, 2011;Edwards et al, 2012;Griswold et al, 2012).…”