We show a paternally inherited miR-873-5p variant with altered binding affinity for several risk-genes including NRXN2 and CNTNAP2 putatively overlay maternally inherited loss-of-function coding variations in NRXN1 and CNTNAP2 to likely increase the genetic liability in an idiopathic ASD case.
To assess its population impact we studied 2148 common single nucleotide polymorphisms (SNPs) using transmission disequilibrium test (TDT) across the entire ~3.3 Mb CNTNAP2 locus in 186 (408 trios) multiplex and 323 simplex families with autistic spectrum disorder (ASD).
These findings reveal a key contribution of ASD-associated gene CNTNAP2 in modulating macroscale functional connectivity, and suggest that homozygous loss-of-function mutations in this gene may predispose to neurodevelopmental disorders and autism through a selective dysregulation of connectivity in integrative prefrontal areas.
A total of 110 adult patients with ASD (n=61) or ADHD (n=49) with or without a lifetime history of SUD participated in a study in which we genotyped polymorphisms in five known candidate genes for (one of) the disorders, i.e. the 5HTTLPR in SLC6A4/5-HTT, rs1800497 (TaqIA C>T) in DRD2, rs7794745 in CNTNAP2, rs1843809 in TPH2, and rs6565113 in CDH13.
Mice deficient in Cntnap2 (Cntnap2-/- mice) show core ASD-like phenotypes, and have been demonstrated as a validated model for ASD-relevant drug discovery.
These findings suggest a partially shared etiology between ASDs and SM and raise questions about which aspects of these syndromes are potentially influenced by CNTNAP2 and mechanism(s) by which these influences may be conveyed.
Loss of one Cntnap2 allele is sufficient to elicit axonal growth alteration, revealing a situation that may be relevant for CNTNAP2 heterozygosity in ASD patients.
Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized.
Although genetic variations in several genes encoding for synaptic adhesion proteins have been found to be associated with autism spectrum disorders, one of the most consistently replicated genes has been CNTNAP2, encoding for contactin-associated protein-like 2 (CASPR2), a multidomain transmembrane protein of the neurexin superfamily.
Nonetheless, when viewed in light of two independent studies published in this issue of AJHG showing a relationship between ASD and common CNTNAP2 alleles, the cytogenetic and mutation screening data suggest that rare variants may also contribute to the pathophysiology of ASD, but place limits on the magnitude of this contribution.
Considering that Cntnap2 shows high expression levels in the striatum during human and mouse embryonic development and that the cortico-striato-thalamic circuitry is important for speech and language development, alterations in striatal PV expression and associated (homeostatic) adaptations are likely to play an important role in <i>Cntnap2-/-</i> mice and, assumingly, in human ASD patients with known Cntnap2 mutations.
These findings demonstrate that risk associated variation in the CNTNAP2 gene impacts on brain activation in healthy non-autistic individuals during a language processing task providing evidence of the effect of genetic variation in CNTNAP2 on a core feature of ASDs.
Comparison of disruptions of CNTNAP2 in patients with GTS and ASD suggests that large proximal disruptions result in either GTS or ASD, while relatively small distal disruptions may be phenotypically neutral.
Contactin-associated protein-like 2 (<i>CNTNAP2</i>) is an ASD-associated gene, and while <i>Cntnap2</i> knockout (KO) mice recapitulate many of the features of ASD, the effect on cortical circuitry is poorly understood.
Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations.
Loss-of-function mutations in CNTNAP2 cause a syndromic form of autism spectrum disorder in humans and produce social deficits, repetitive behaviors, and seizures in mice.
Heterozygous copy-number and missense variants in CNTNAP2 and NRXN1 have repeatedly been associated with a wide spectrum of neuropsychiatric disorders such as developmental language and autism spectrum disorders, epilepsy and schizophrenia.