Abstract
The contactin-associated protein-like 2 (CNTNAP2) gene is a member of the neurexin superfamily. CNTNAP2 was first implicated in the cortical dysplasia-focal epilepsy (CDFE) syndrome, a recessive disease characterized by intellectual disability, epilepsy, language impairments and autistic features. Associated SNPs and heterozygous deletions in CNTNAP2 were subsequently reported in autism, schizophrenia and other psychiatric or neurological disorders. We aimed to comprehensively examine evidence for the role of CNTNAP2 in susceptibility to psychiatric disorders, by the analysis of multiple classes of genetic variation in large genomic datasets. In this study we used: i) summary statistics from the Psychiatric Genomics Consortium (PGC) GWAS for seven psychiatric disorders; ii) examined all reported CNTNAP2 structural variants in patients and controls; iii) performed cross-disorder analysis of functional or previously associated SNPs; and iv) conducted burden tests for pathogenic rare variants using sequencing data (4,483 ASD and 6,135 schizophrenia cases, and 13,042 controls). The distribution of CNVs across CNTNAP2 in psychiatric cases from previous reports was no different from controls of the database of genomic variants. Gene-based association testing did not implicate common variants in autism, schizophrenia or other psychiatric phenotypes. The association of proposed functional SNPs rs7794745 and rs2710102, reported to influence brain connectivity, was not replicated; nor did predicted functional SNPs yield significant results in meta-analysis across psychiatric disorders at either SNP-level or gene-level. Disrupting CNTNAP2 rare variant burden was not higher in autism or schizophrenia compared to controls. Finally, in a CNV mircroarray study of an extended bipolar disorder family with 5 affected relatives we previously identified a 131kb deletion in CNTNAP2 intron 1, removing a FOXP2 transcription factor binding site. Quantitative-PCR validation and segregation analysis of this CNV revealed imperfect segregation with BD.This large comprehensive study indicates that CNTNAP2 may not be a robust risk gene for psychiatric phenotypes.
Highlights
The contactin-associated protein-like 2 (CNTNAP2) is located on chromosome 7q35-36.1, and consists of 24 exons spanning 2.3Mb, making it one of the largest protein coding genes in the human genome
Genetic mutations that disrupt both copies of the CNTNAP2 gene lead to severe disease, characterized by profound intellectual disability, epilepsy, language difficulties and autistic traits, leading to the hypothesis that this gene may be involved in autism given some overlapping clinical features with this disease
Several large DNA deletions affecting one of the two copies of CNTNAP2 were found in some patients with autism, and later in patients with schizophrenia, bipolar disorder, attention-deficit hyperactivity-disorder (ADHD) and epilepsy, suggesting that this gene was implicated in several psychiatric or neurologic diseases
Summary
The contactin-associated protein-like 2 (CNTNAP2) is located on chromosome 7q35-36.1, and consists of 24 exons spanning 2.3Mb, making it one of the largest protein coding genes in the human genome. This gene encodes the CASPR2 protein, related to the neurexin superfamily, which localises with potassium channels at the juxtaparanodal regions of the Ravier nodes in myelinated axons, playing a crucial role in the clustering of potassium channels required for conduction of axon potentials [1]. The crucial role of CNTNAP2 in the human brain became clear in 2006 when Strauss et al, reported homozygous mutations in Old Order Amish families segregating with a severe Mendelian condition, described as cortical dysplasiafocal epilepsy (CDFE) syndrome (OMIM 610042) [5]. The phenotype is often accompanied by dysmorphic features, autistic traits, psychomotor delay and focal cortical dysplasia
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