Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders

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.

FIG. 1

Illustrates the size and range of the 12 deletion CNVs in relation to the exons and protein domains of NRXN1-α and -β in the UCSC Genome Browser (http://genome.ucsc.edu) [Kent et al., 2002]. The top track shows the genomic position and size of the 12 deletion CNVs. The middle tracks show the gene annotations in RefSeq and Ensembl. The Refseq Genes show the α and β isoforms of the NRXN1 gene; the Ensembl gene prediction shows several other minor isoforms of the NRXN1 gene. The bottom panel shows the protein domains of the NRXN1-α gene product. SP, signal peptide; LNS, laminin/neurexin/sex hormone-binding globulin domain; EGF, epithelium growth factor like domain; OS, O-glycosylation sequence; TM, transmembrane domain; CT, cytoplasmic tail. [Color figure can be viewed in the online issue, which is available at http://www.interscience.wiley.com.]

FIG. 2

A: NRXN1-α deletions segregate with autism spectrum disorder (ASD) and mild mental retardation. Pedigree 1 shows co-segregation of a hemizygous CNV between rs17041500 and rs17512199 which deletes the first three coding exons (Del Ex1-3) of NRXN1-α. The CNV is carried by all subjects with ASD and diminished intelligence quotient (IQ), but not by a typically developing sibling. Pedigree 2 shows co-segregation of a hemizygous CNV which deletes likely regulatory, genomic DNA upstream (Del 5′Reg) of NRXN1-α. PDD-NOS, pervasive development disorder, not otherwise specified. +, wild-type, non-deleted DNA. B: Mapping of inferred CN data SNP-by-SNP on the UCSC genome browser demonstrates the extent across the NRXN1 locus. Vertical red lines indicate each SNP with copy number of 1 or 2. Horizontal green lines demarcate the extent of each deletion. Alignment of annotated genes in the RefSeq database are shown as well as a representation of vertebrate conservation using multiz and related tools in the UCSC/Penn State Bioinformatics comparative genomic alignment pipeline. Of note, Del 5′Reg deletes the last four exons of an uncharacterized, spliced mRNA AK127244 that is expressed in brain. The gene is transcribed in the opposite direction as NRXN1-α yet the transcription start site is within 3.5 kb suggesting that this mRNA may be transcribed coordinately with NRXN1-α. [Color figure can be viewed in the online issue, which is available at http://www.interscience.wiley.com.]