Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders

Abstract

Based on genomic rearrangements and copy number variations, the contactin-associated protein-like 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, and attention deficit hyperactivity disorder. To explain the phenotypic pleiotropy of CNTNAP2 alterations, several hypotheses have been put forward. Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins. Also exome sequencing, which covers <0.2% of the CNTNAP2 genomic DNA, has revealed numerous single nucleotide variants in healthy individuals and in patients with neurodevelopmental disorders. In some of these disorders, disruption of CNTNAP2 may be interpreted as a susceptibility factor rather than a directly causative mutation. In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. This review discusses the impact of CNTNAP2 mutations on its functioning at multiple levels of the combinatorial genetic networks that govern brain development. In addition, recommendations for genomic testing in the context of clinical genetic management of patients with neurodevelopmental disorders and their families are put forward.

Single nucleotide polymorphisms in the CNTNAP2 gene in Brazilian patients with autistic spectrum disorder

“…Genetic variations and abnormal gene expression of CNTNAP2 may increase the risks for specific language impairments by altering brain function during linguistic processing, which could result in manifestations such as found in individuals with ASD (Rodenas-Cuadrado et al, 2014). A positive association between the TT genotype and predisposition for autism has been observed by other researchers (Arking et al, 2008;Tan et al, 2010;Poot, 2015). Therefore, based on the results of our study, we suggest that a common variant of CNTNAP2 (genotype TT for rs7794745) can contribute to susceptibility to autism, which is in agreement with previous findings.…”

“…Converging evidence suggests that the CNTNAP2 gene is a strong candidate gene for predisposition to autism (Stein et al, 2011;Peñagarikano and Geschwind, 2012;Poot, 2015). Common genomic variants of CNTNAP2 have been associated with autism as well as related phenotypes such as impaired language function, abnormal social behavior, intellectual deficiency, epilepsy, and schizophrenia (Bakkaloglu et al, 2008;Friedman et al, 2008;Betancur, 2011;Miles, 2011;Angelidou et al, 2012).…”

“…However, genome-wide association studies have amassed evidence suggesting the involvement of hundreds of genes and their associated genetic pathways (Loke et al, 2015). Research reveals that non-syndromic cases may have multiple genomic components, which suggests that investigations of underlying susceptibility genes in autism may be somewhat challenging (Sokolowsky et al, 2012;Poot, 2015).…”

“…Based on genomic rearrangements and copy number variations, the CNTNAP2 gene has been implicated in predisposition to neurodevelopmental disorders such as autism. Exome sequencing, which covers <0.2% of the CNTNAP2 genomic DNA, has revealed numerous SNP in healthy individuals and in patients with neurodevelopmental disorders (Peñagarikano and Geschwind, 2012;Clemm von Hohenberg et al, 2013;Poot, 2015).…”

SHANK Mutations May Disorder Brain Development

“…Thus, mutations of SHANK3 , provoking haploinsufficiency or triplosufficiency, are sufficient to elicit a clinical phenotype. Such a dominant effect of mutations suggests that SHANK3 may be a node in a combinatorial genetic network, as for instance CNTNAP2 [Poot et al, 2011;Poot, 2015]. It remains conceivable, however, that some mutations of SHANK3 may alone be sufficient to elicit a clinical disorder.…”