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Children's Hospital Boston Genotype Phenotype Study Group: Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders

Division of Developmental Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.27). 06/2010; 153B(4):937-47. DOI: 10.1002/ajmg.b.31063
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ABSTRACT Research has implicated mutations in the gene for neurexin-1 (NRXN1) in a variety of conditions including autism, schizophrenia, and nicotine dependence. To our knowledge, there have been no published reports describing the breadth of the phenotype associated with mutations in NRXN1. We present a medical record review of subjects with deletions involving exonic sequences of NRXN1. We ascertained cases from 3,540 individuals referred clinically for comparative genomic hybridization testing from March 2007 to January 2009. Twelve subjects were identified with exonic deletions. The phenotype of individuals with NRXN1 deletion is variable and includes autism spectrum disorders, mental retardation, language delays, and hypotonia. There was a statistically significant increase in NRXN1 deletion in our clinical sample compared to control populations described in the literature (P = 8.9 x 10(-7)). Three additional subjects with NRXN1 deletions and autism were identified through the Homozygosity Mapping Collaborative for Autism, and this deletion segregated with the phenotype. Our study indicates that deletions of NRXN1 predispose to a wide spectrum of developmental disorders.

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    • "Treatment of PC12 cells with PPA or BA caused down regulation of FMR1 gene expression (Table 10). Neurexin 1 (NRXN1) is another gene considered to be causal for ASD [127], [128] which was also down regulated following BA administration. Many genes associated with ASD are also involved in the neuroligin-neurexin interaction at the glutamate synapse [129], [28]. "
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    • "(Boucard et al., 2005). Recent data suggest that heterozygous mutations in NRXN1 represent a susceptibility factor for a broad spectrum of neurological and neuropsychological disorders for example, schizophrenia (Ching et al., 2010; Kirov et al., 2008; Rujescu et al., 2009), ID disorders (McIntosh et al., 2006; Zahir et al., 2008; Zweier et al., 2009), autism, (Gregor et al., 2011) and various other neuropsychiatric disorders (Ching et al., 2010). A number of studies reveal recessive genetic defects in NRXN1 associated with severe ID and dysmorphic features resembling the Pitt–Hopkins like syndrome in some cases (Duong et al., 2012; Harrison et al., 2011; Zweier et al., 2009). "
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    • "The outcome of the autism genome-wide association study projects surprisingly revealed only weak correlations for ASD to common genetic variants, but identified genes with rare single nucleotide polymorphisms (SNPs) or copy number variations that have a considerable impact [96]. Such rare mutations have been found in the α-neurexin coding region of nrxn1[97-99], nrxn3[100] and the signal peptide of β-neurexins [101]. An excess of mutations in these genes is found in patients with ASD [27,102], schizophrenia [103,104] and substance abuse and impulsive behavior [105]. "
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