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      NRXN1 deletions identified by array comparative genome hybridisation in a clinical case series - further understanding of the relevance of NRXN1 to neurodevelopmental disorders.

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          Abstract

          Microdeletions in the NRXN1 gene have been associated with a range of neurodevelopmental disorders, including autism spectrum disorders, schizophrenia, intellectual disability, speech and language delay, epilepsy and hypotonia.

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          Structural variation of chromosomes in autism spectrum disorder.

          Christian Marshall, Abdul Noor, John Vincent … (2008)
          Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
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            Disruption of neurexin 1 associated with autism spectrum disorder.

            Hyung-Goo Kim, Shotaro Kishikawa, Anne W. Higgins … (2008)
            Autism is a neurodevelopmental disorder of complex etiology in which genetic factors play a major role. We have implicated the neurexin 1 (NRXN1) gene in two independent subjects who display an autism spectrum disorder (ASD) in association with a balanced chromosomal abnormality involving 2p16.3. In the first, with karyotype 46,XX,ins(16;2)(q22.1;p16.1p16.3)pat, NRXN1 is directly disrupted within intron 5. Importantly, the father possesses the same chromosomal abnormality in the absence of ASD, indicating that the interruption of alpha-NRXN1 is not fully penetrant and must interact with other factors to produce ASD. The breakpoint in the second subject, with 46,XY,t(1;2)(q31.3;p16.3)dn, occurs approximately 750 kb 5' to NRXN1 within a 2.6 Mb genomic segment that harbors no currently annotated genes. A scan of the NRXN1 coding sequence in a cohort of ASD subjects, relative to non-ASD controls, revealed that amino acid alterations in neurexin 1 are not present at high frequency in ASD. However, a number of rare sequence variants in the coding region, including two missense changes in conserved residues of the alpha-neurexin 1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggest that even subtle changes in NRXN1 might contribute to susceptibility to ASD.
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              Splicing in action: assessing disease causing sequence changes.

              M Baralle, D. Baralle (2005)
              Variations in new splicing regulatory elements are difficult to identify exclusively by sequence inspection and may result in deleterious effects on precursor (pre) mRNA splicing. These mutations can result in either complete skipping of the exon, retention of the intron, or the introduction of a new splice site within an exon or intron. Sometimes mutations that do not disrupt or create a splice site activate pre-existing pseudo splice sites, consistent with the proposal that introns contain splicing inhibitory sequences. These variants can also affect the fine balance of isoforms produced by alternatively spliced exons and in consequence cause disease. Available genomic pathology data reveal that we are still partly ignorant of the basic mechanisms that underlie the pre-mRNA splicing process. The fact that human pathology can provide pointers to new modulatory elements of splicing should be exploited.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): J Mol Psychiatry
                Title: Journal of molecular psychiatry
                Publisher: Springer Science and Business Media LLC
                ISSN: 2049-9256
                ISSN (Print): 2049-9256
                Publication date (Electronic): 2013
                Volume: 1
                Issue: 1
                Affiliations
                [1 ] Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Kings College London, De Crespigny Park, Denmark Hill, London, SE5 8AF UK.
                [2 ] Cytogenetics Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.
                [3 ] MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF UK.
                Article
                Publisher Item ID: 4
                DOI: 10.1186/2049-9256-1-4
                PMC ID: 4223877
                PubMed ID: 25408897
                SO-VID: 04570717-d889-416d-a642-e31c528b610a
                History

                Keywords: Neurexins,Neurodevelopmental disorders,Autism spectrum disorders,Copy number variants,Epilepsy,Microcephaly,NRXN1
                Data availability:
                Keywords: Neurexins, Neurodevelopmental disorders, Autism spectrum disorders, Copy number variants, Epilepsy, Microcephaly, NRXN1

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