Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions

Abstract

Copy number variants (CNVs) and intragenic rearrangements of the NRXN1 (neurexin 1) gene are associated with a wide spectrum of developmental and neuropsychiatric disorders, including intellectual disability, speech delay, autism spectrum disorders (ASDs), hypotonia and schizophrenia. We performed a detailed clinical and molecular characterization of 24 patients who underwent clinical microarray analysis and had intragenic deletions of NRXN1. Seventeen of these deletions involved exons of NRXN1, whereas seven deleted intronic sequences only. The patients with exonic deletions manifested developmental delay/intellectual disability (93%), infantile hypotonia (59%) and ASDs (56%). Congenital malformations and dysmorphic features appeared infrequently and inconsistently among this population of patients with NRXN1 deletions. The more C-terminal deletions, including those affecting the β isoform of neurexin 1, manifested increased head size and a high frequency of seizure disorder (88%) when compared with N-terminal deletions of NRXN1.

Figure 1

Intragenic deletions in NRXN1 identified by exon-targeted aCGH. (a) The α and β isoforms of NRXN1 are shown. Aligned with these is a plot of array probe density, demonstrating enhanced resolution within and surrounding exons of the gene. The X-coordinate of each dot corresponds to the genomic position midway between two consecutive probes; the Y-coordinate is the genomic distance between these probes. (b) Twenty-four intragenic deletions of NRXN1, aligned to the α and β isoforms of NRXN1. Exonic deletions are shown in red, intronic deletions in orange. Each box indicates the patient ID (E1–E17 for exonic deletions, I1–I7 for intronic deletion cases). Plotting is based on UCSC Genome Build hg18 and the minimum interval detected to be deleted by aCGH.

Figure 2

Box plot of Z-scores for head circumference of individuals with N- and C-terminal exon deletions of NRXN1. Comparing the N-terminal cases of NRXN1 deletions (involving the first five exons) and the C-terminal cases of NRXN1 deletions (exons six and higher) reveals a significant difference in head size between the two groups (unpaired t-test, P=0.0003). Y-coordinates correspond to the Z-score for head circumference (sex and age matched).