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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    • "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.
    Journal of Neural Transmission 11/2015; DOI:10.1007/s00702-015-1458-5 · 2.40 Impact Factor
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    • "Although the number of causative genes for ASD could be more than 250, [Huguet et al., 2013] they affect a restricted number of biological pathways, including chromatin remodeling, mRNA translation and synaptic functions, [Toro et al., 2010; De Rubeis et al., 2013; Iossifov et al., 2014]. Among the synaptic genes associated with ASD, Ig-like cell adhesion molecules such as CNTN3 [Girirajan et al., 2011], CNTN4 [Fernandez et al., 2004] and CNTNAP2 [Alarcon et al., 2008; Arking et al., 2008] have important roles in neuronal interactions for synaptic targeting, neuronal migration, and axon guidance. Neurotrimin (NTM), which belongs to the same molecular family, is a glycosylphosphatidylinositol (GPI)-anchored cell adhesion protein and a member of the IgLON subfamily (containing also LAMP and OBCAM). "
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    ABSTRACT: Jacobsen syndrome (JS) is characterized by intellectual disability and higher risk for autism spectrum disorders (ASD). All patients with JS are carriers of contiguous de novo deletions of 11q24.2-25, but the causative genes remain unknown. Within the critical interval, we hypothesized that haploinsufficiency of the neuronal cell adhesion molecule Neurotrimin (NTM) might increase the risk for ASD and could affect brain structure volumes. We searched for deleterious mutations affecting NTM in 1256 ASD patients and 1287 controls, using SNP arrays, and by direct sequencing of 250 ASD patients and 180 controls. We compared our results to those obtained from independent cohorts of ASD patients and controls. We identified two patients with Copy Number Variants (CNV) encompassing NTM, one with a large de novo deletion, and a clinical phenotype of JS (including macrocephaly), and a second with a paternally inherited duplication, not consistent with JS. Interestingly, no similar CNVs were observed in controls. We did not observe enrichment for deleterious NTM mutations in our cohort. We then explored if the macrocephaly in the patient with JS was associated with a homogeneous increase of brain structures volumes using automatic segmentation. Compared to subjects without NTM micro-rearrangements (n=188), the patient had an increased volume of the sub-cortical structures but a decrease of the occipital gray matter. Finally our explorations could not incriminate NTM as a susceptibility gene for ASD, but provides new information on the impact of the 11q24.2-25 deletion on brain anatomy. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2015; DOI:10.1002/ajmg.a.37345 · 2.16 Impact Factor
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    • "Genetics has already informed pharmacological treatment exploration for ASD ( Jeste and Geschwind, 2014). For example , CNTNAP2 variants have been associated with ASD and other neurodevelopmental disorders (Alarcon et al., 2008; Arking et al., 2008); this variant has been shown to have increased expression in frontostriatal circuits of the brain (Abrahams et al., 2007). CNTNAP2-mutant mouse models, which present ASD-like symptoms, have shown alleviated repetitive behaviors, but no change in social deficits when treated with risperidone, a dopamine antagonist (Penagarikano et al., 2011; Penagarikano and Geschwind, 2012). "
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    ABSTRACT: Complex diseases are caused by a combination of genetic and environmental factors, creating a difficult challenge for diagnosis and defining subtypes. This review article describes how distinct disease subtypes can be identified through integration and analysis of clinical and multi-omics data. A broad shift toward molecular subtyping of disease using genetic and omics data has yielded successful results in cancer and other complex diseases. To determine molecular subtypes, patients are first classified by applying clustering methods to different types of omics data, then these results are integrated with clinical data to characterize distinct disease subtypes. An example of this molecular-data-first approach is in research on Autism Spectrum Disorder (ASD), a spectrum of social communication disorders marked by tremendous etiological and phenotypic heterogeneity. In the case of ASD, omics data such as exome sequences and gene and protein expression data are combined with clinical data such as psychometric testing and imaging to enable subtype identification. Novel ASD subtypes have been proposed, such as CHD8, using this molecular subtyping approach. Broader use of molecular subtyping in complex disease research is impeded by data heterogeneity, diversity of standards, and ineffective analysis tools. The future of molecular subtyping for ASD and other complex diseases calls for an integrated resource to identify disease mechanisms, classify new patients, and inform effective treatment options. This in turn will empower and accelerate precision medicine and personalized healthcare.
    Omics: a journal of integrative biology 04/2015; 19(4):197-208. DOI:10.1089/omi.2015.0020 · 2.36 Impact Factor
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