A Common Genetic Variant in the Neurexin Superfamily Member CNTNAP2 Increases Familial Risk of Autism

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2008; 82(1):160-4. DOI: 10.1016/j.ajhg.2007.09.015
Source: PubMed


Autism is a childhood neuropsychiatric disorder that, despite exhibiting high heritability, has largely eluded efforts to identify specific genetic variants underlying its etiology. We performed a two-stage genetic study in which genome-wide linkage and family-based association mapping was followed up by association and replication studies in an independent sample. We identified a common polymorphism in contactin-associated protein-like 2 (CNTNAP2), a member of the neurexin superfamily, that is significantly associated with autism susceptibility. Importantly, the genetic variant displays a parent-of-origin and gender effect recapitulating the inheritance of autism.

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Available from: Dan E Arking, Dec 05, 2014
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    • "Many of these studies have focused on ASD, and using linkage and genome-wide association studies (GWAS) as well as copy number variation (CNV) analyses have clearly associated between Caspr2 and ASD (Alarcon et al., 2008; Arking et al., 2008; Bakkaloglu et al., 2008; Li et al., 2010; O'Roak et al., 2011). Additionally, common variants in Caspr2 have also been associated with ASD (Anney et al., 2012; Arking et al., 2008; Stein et al., 2011). Numerous mutations in Caspr2 have been identified, in many different regions of the protein, both intra-and extra-cellularly, and have been associated with ASD (Bakkaloglu et al., 2008). "
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    ABSTRACT: Genome-wide association studies and copy number variation analyses have linked contactin associated protein 2 (Caspr2, gene name Cntnap2) with autism spectrum disorder (ASD). In line with these findings, mice lacking Caspr2 (Cntnap2(-/-)) were shown to have core autism-like deficits including abnormal social behavior and communication, and behavior inflexibility. However the role of Caspr2 in ASD pathogenicity remains unclear. Here we have generated a new Caspr2:tau-LacZ knock-in reporter line (Cntnap2(tlacz/tlacz)), which enabled us to monitor the neuronal circuits in the brain expressing Caspr2. We show that Caspr2 is expressed in many brain regions and produced a comprehensive report of Caspr2 expression. Moreover, we found that Caspr2 marks all sensory modalities: it is expressed in distinct brain regions involved in different sensory processings and is present in all primary sensory organs. Olfaction-based behavioral tests revealed that mice lacking Caspr2 exhibit abnormal response to sensory stimuli and lack preference for novel odors. These results suggest that loss of Caspr2 throughout the sensory system may contribute to the sensory manifestations frequently observed in ASD.
    Full-text · Article · Dec 2015 · Molecular and Cellular Neuroscience
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    • "In particular, two CNTNAP2 gene variants, rs7794745 (intron 2) and rs2710102 (intron 13) are frequently discussed to play a role in ASD as well as language disabilities (Chiocchetti et al. 2014). The noncoding variant, rs7794745 (T/A, presumed risk allele T) was found to associate with an increased risk for ASD (Arking et al. 2008; Sampath et al. 2013). Other intronic SNPs, such as rs2710102, have been identified to be associated with the quantitative autism endophenotypes of age-at-first word (p = 0.0006) (Alarcón et al. 2008) and specific language impairment (p = 0.002–5 9 10 -5 ) (Vernes et al. 2008) (C/T, presumed risk allele C). "
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    ABSTRACT: The Contactin Associated Protein-like 2 (CNTNAP2) gene has been discussed to be associated with different symptoms of autism spectrum disorders (ASDs) and other neurodevelopmental disorders. We aimed to elucidate the genetic association of CNTNAP2 within high functioning ASD (HFA), focusing on autism specific symptoms and reducing intelligence related factors. Furthermore, we compared our findings conducting a meta-analysis in patients with ASD and HFA only. A case-control association study was performed for HFA (HFA, n = 105; controls, n = 133). Moreover, we performed a family-based association study (DFAM) analysis (HFA, n = 44; siblings, n = 57). Individuals were genotyped for the two most frequently reported single nucleotide polymorphisms (SNPs) in the CNTNAP2 gene (rs2710102, rs7794745). Furthermore, a meta-analysis using the MIX2 software integrated our results with previously published data. A significant association for the carriers of the T-allele of the rs7794745 with HFA was found in the case-control sample [OR = 1.547; (95 % CI 1.056-2.266); p = 0.025]. No association could be found by DFAM with any of the CNTNAP2 SNPs with HFA. The meta-analysis of both SNPs did not show a significant association with either ASD or with HFA. Overall, including case-control, sibs, and meta-analysis, we could not detect any significant association with the CNTNAP2 gene and HFA. Our results point in the direction that CNTNAP2 may not play a major role in HFA, but rather seems to have a significance in neurodevelopmental disorders or in individuals displaying intellectual delays.
    Full-text · Article · Nov 2015 · Journal of Neural Transmission
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    • "Contactin-associated protein-like 2 (CNTNAP2) is a gene of great interest in the study of autism spectrum disorder (ASD) as well as specific language impairment (SLI), based on evidence from genetic epidemiological and molecular studies (Alarcón et al., 2008;Arking et al., 2008;Bakkaloglu et al., 2008;Nord et al., 2011;Rodenas-Cuadrado, Ho, & Vernes, 2014;Strauss et al., 2006;Vernes et al., 2008). Behaviorally, genetic variants of CNTNAP2 are associated with language-related endophenotypes such as age at language onset, nonword repetition, and expressive and receptive language abilities (seeCuadrado et al., 2014, for review). "
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    ABSTRACT: Genetic epidemiological studies support a role for CNTNAP2 in developmental language disorders such as autism spectrum disorder, specific language impairment, and dyslexia. Atypical language development and function represent a core symptom of autism spectrum disorder (ASD), with evidence suggesting that aberrant auditory processing-including impaired spectrotemporal processing and enhanced pitch perception-may both contribute to an anomalous language phenotype. Investigation of gene-brain-behavior relationships in social and repetitive ASD symptomatology have benefited from experimentation on the Cntnap2 knockout (KO) mouse. However, auditory-processing behavior and effects on neural structures within the central auditory pathway have not been assessed in this model. Thus, this study examined whether auditory-processing abnormalities were associated with mutation of the Cntnap2 gene in mice. Cntnap2 KO mice were assessed on auditory-processing tasks including silent gap detection, embedded tone detection, and pitch discrimination. Cntnap2 knockout mice showed deficits in silent gap detection but a surprising superiority in pitch-related discrimination as compared with controls. Stereological analysis revealed a reduction in the number and density of neurons, as well as a shift in neuronal size distribution toward smaller neurons, in the medial geniculate nucleus of mutant mice. These findings are consistent with a central role for CNTNAP2 in the ontogeny and function of neural systems subserving auditory processing and suggest that developmental disruption of these neural systems could contribute to the atypical language phenotype seen in autism spectrum disorder. (PsycINFO Database Record
    Full-text · Article · Oct 2015 · Behavioral Neuroscience
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