Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

Abstract

Copy number variants (CNVs) have repeatedly been found to cause or predispose to autism spectrum disorders (ASDs). For diagnostic purposes, we screened 194 individuals with ASDs for CNVs using Illumina SNP arrays. In several probands, we also analyzed candidate genes located in inherited deletions to unmask autosomal recessive variants. Three CNVs, a de novo triplication of chromosome 15q11-q12 of paternal origin, a deletion on chromosome 9p24 and a de novo 3q29 deletion, were identified as the cause of the disorder in one individual each. An autosomal recessive cause was considered possible in two patients: a homozygous 1p31.1 deletion encompassing PTGER3 and a deletion of the entire DOCK10 gene associated with a rare hemizygous missense variant. We also identified multiple private or recurrent CNVs, the majority of which were inherited from asymptomatic parents. Although highly penetrant CNVs or variants inherited in an autosomal recessive manner were detected in rare cases, our results mainly support the hypothesis that most CNVs contribute to ASDs in association with other CNVs or point variants located elsewhere in the genome. Identification of these genetic interactions in individuals with ASDs constitutes a formidable challenge.

Recent Advances in the Genetics of Schizophrenia

“…Deletion and duplication cause microcephaly and macrocephaly, respectively, and schizophrenia is only one of many associated neurodevelopmental phenotypes [54]. The 3q29 deletion was first described to cause mental retardation, with slight dysmorphic facial features [55] and in some cases autism [56] and was later linked to schizophrenia [57-59]. The 7q11.23 duplication is reciprocal to the Williams-Beuren syndrome deletion [60] and in addition to schizophrenia has been associated with autism, language delay, and mental retardation [61].…”

Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

“…This function of Caspr2 in neural development is comparable to the involvement of the neural cell-adhesion molecules contactin 4, contactin 5 and contactin 6 in brain development [Mercati et al, 2013]. Disruptions in these contactin genes confer an increased risk for ASD [van Daalen et al, 2011;Nava et al, 2014]. Likewise, loss of Caspr2 function may contribute to the ASD found in several patients with CNVs in CNTNAP2 [Zweier et al, 2007;Alarcon et al, 2008;Poot et al, 2010].…”

Manduca Contactin Regulates Amyloid Precursor Protein-Dependent Neuronal Migration

“…Several Contactins have also been implicated in the control of neuronal migration, although this function may be partially due to their effects on neuronal proliferation and differentiation (Denaxa et al, 2005;Ma et al, 2008;Wang et al, 2011;Xenaki et al, 2011). Similarly, both APP and Contactins have been linked with a variety of neurodevelopmental and age-related disorders: genetic mutations affecting Contactin-3, Contactin-4, Contactin-5, and Contactin-6 are strongly associated with autism spectrum disorders (ASDs; Zuko et al, 2013;Mohebiany et al, 2014;Nava et al, 2014;Hu et al, 2015), while elevated sAPP levels have been identified as potential biomarkers for the most severe forms of ASD (Sokol et al, 2006;Ray et al, 2011).…”

“…It has been postulated that an authentic APP ligand might stimulate the proteolytic cleavage of the holoprotein by one or more secretases (O'Brien and Wong, 2011;Zheng and Koo, 2011). Accordingly, we also tested whether treating embryos with MsCont-Fc altered the relative abundance of full-length or cleaved forms of APPL (quantified by our Western blotting methods).…”