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 × 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. © 2010 Wiley-Liss, Inc.

Phenotypic spectrum and genotype–phenotype correlations of NRXN1 exon deletions

“…While growth parameters were within normal limits overall, both average height (34th percentile; SEM ¼ 5.5) and average weight (34th percentile; SEM ¼ 8.7) were slightly decreased when compared with the general population, based on CDC growth charts. 24 The average head circumference was on the 60th percentile (SEM ¼ 8.3). Mild dysmorphic features were reported in several patients, but no characteristic facial or physical phenotype was noted across individuals within this cohort (Table 2).…”

“…[13][14][15]21,23 More recently, intragenic rearrangements of NRXN1 have been described and associated with a wide spectrum of developmental disorders. 23,24 There is a significantly higher prevalence of NRXN1 deletions among clinical samples when compared with control populations. In the reported cohort, the incidence of intragenic NRXN1 deletions was 20/8051 among clinically referred cases (0.25%), which is quasi identical to the rate reported by Ching et al (9/3450; ie, 0.25%).…”

“…Neurexin 1-b deletions seem much less common overall. 24 Tandem intragenic duplications of NRXN1-b sequences in two families were associated to autistic phenotypes and cognitive delays. 23 This study set out to characterize cases of small, intragenic deletions of NRXN1 both clinically and molecularly, and to determine whether genotype-phenotype correlations exist within this cohort.…”

“…Their phenotypes are reported as variable, including ASDs, mental retardation, language delays and hypotonia. 24 Both CNVs deleting the entire NRXN1 gene and multiexonic deletions of NRXN1-a have been described. Neurexin 1-b deletions seem much less common overall.…”

Implications of gene copy-number variation in health and diseases

“…Variants comprising a variety of mutations such as missense mutation, translocation, whole-gene deletion and intra-genic copy number changes result into a significant association with a variety of phenotypic changes such as autism, schizophrenia (SZ) and nicotine dependence. 26 Autism Autism is a pervasive neurodegenerative disorder characterized by impaired communication or linguistic skills, social interaction, cognition, some form of repetitive and restricted stereotyped interest, ritual or other behavior. The symptoms vary from person-to-person and no two persons have identical symptoms and hence called Autism spectrum disorder.…”