Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families

Abstract

Autism or autism spectrum disorder (ASD) is a range of neurodevelopmental disorders starting in early childhood and is characterized by impairments in communication and reciprocal social interaction and presence of restricted and repetitive patterns of behavior. The contribution of genetic factors to autism is clear in twin and family studies. It is apparent that, overall, ASD is a complex non-Mendelian disorder. Recent studies suggest that copy number variations (CNVs) play a significant role in the etiology of ASD. For the current work, we recruited 245 family members from 73 ASD families from Styria, Austria. The DNA from probands was genotyped with Affymetrix single nucleotide polymorphism (SNP) 6.0 microarrays to screen for CNVs in their genomes. Analysis of the microarray data was performed using three different algorithms, and a list of stringent calls was compared to existing CNV data from over 2,357 controls of European ancestry. For stringent calls not present in controls, quantitative real-time PCR (qRT-PCR) was used to validate the CNVs in the probands and in their family members. Twenty-two CNVs were validated from this set (five of which are apparently de novo), many of which appear likely to disrupt genes that may be considered as good candidates for neuropsychiatric disorders, including DLG2, S100B, ARX, DIP2A, HPCAL1, and GPHN. Several others disrupt genes that have previously been implicated in autism, such as BDNF, AUTS2, DPP6, and C18orf22, and our data add to the growing evidence of their involvement in ASD.

Copy number variation in Han Chinese individuals with autism spectrum disorder

“…This represents a de novo CNV rate of 8.6% (8/93), similar to that which has been seen previously in other non-Chinese CNV studies [2-4,12]. In one female proband (683-3), we discovered a 22-kb deletion at 2q37.1 overlapping GIGYF2 , which lies in a susceptibility locus for familial Parkinson's disease [13].…”

“…This deletion lies upstream of the 600-kb ASD-implicated risk locus [1]. Similarly sized deletions have been previously noted in individuals with obesity and developmental delay [12,19]. Unlike many of the individuals with similar deletions, this male has a BMI of 18.26, putting him in the normal range.…”

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

“…Many of these genes we note play critical roles in the nervous system, such as synaptogenesis ( NTM [57]), postsynaptic density scaffolding and signaling ( DLG2 ; e.g., [58]), and axon growth and guidance ( GPM6 A [59]). Additionally, many of these TCF4 target genes have been implicated in genetic studies of autism, intellectual disability, or psychiatric disease (NTM [60]; PDE1C [61]; DLG2 [62]; GPM6A [54,63], suggesting that their aberrant regulation caused by haploinsufficiency of TCF4 may at least in part be involved in the pathophysiology of PTHS. Importantly, each of these genes now provides a functional assay to compare signatures of PTHS patient-derived neurons and the effects of experimental therapeutics as discovered here.…”

Elevated plasma concentrations of S100 calcium-binding protein B and tumor necrosis factor alpha in children with autism spectrum disorders

“…21 In addition, a recent study addressed risk genes for ASD through copy number variation analysis and identified S100B as one of the genes potentially associated with ASD. 22 High concentrations of S100B may be an indicator of glial cell pathology and ongoing damage. However, the scarcity of longitudinal studies prevents us from making further inferences as to whether elevated concentrations of S100B is a cause or a consequence of ASD.…”