Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression

Abstract

Purpose: The purpose of the current study was to assess the penetrance of NRXN1 deletions.

Methods: We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant copy-number variations (CNVs) was used as a proxy to estimate the relative penetrance of NRXN1 deletions.

Results: We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability that were significantly greater than in controls (odds ratio (OR) = 8.14; 95% confidence interval (CI): 2.91-22.72; P < 0.0001). Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3' end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5' NRXN1 deletion (OR = 7.47; 95% CI: 2.36-23.61; P = 0.0006). The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (P = 0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV at a prevalence twice as high as that for exonic NRXN1 deletion cases (P = 0.0035).

Conclusions: The results support the importance of exons near the 5' end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes.Genet Med 19 1, 53-61.

Figure 1. Novel exonic and intronic NRXN1 deletions identified in cases and controls

The image was modified from the Database of Genomic variants (http://dgv.tcag.ca), NCBI Build 37 (hg 19).^, The two primary NRXN1 transcripts (α1 and β1) are shown in pink; other transcripts are not included. The long non-coding RNA (lnRNA) AK127244 is shown in green. Each of the 22 exons is identified by a number according to the NM_004801.4 transcript. The five splice site (SS 1-5) locations are represented above the NRXN1-α transcript. The hollow pink box denoted by a P adjacent to each transcript represents the α and β promoter, respectively. All exonic and intronic deletions (chr2: 50,145,643–51,259,647; hg 19) are represented by solid red and yellow bars, respectively. Deletions with a black grid are subjects that were identified to have a second CNV of potential clinical relevance. Inheritance status of the NRXN1 deletion is represented in brackets following the patient ID number (d.n., de novo; mat, maternal inheritance; pat, paternal inheritance; blank, unknown). P28 and P30 overlap both the 5′ and 3′ ends of NRXN1 and were not included in statistical analyses. P14 and P32 were identified to have maternal uniparental disomy of chromosome 14 and a RAF 1 mutation, respectively. The light blue box designates subjects with deletions overlapping exons ≥5 (3′ deletion). Case numbers were kept consistent throughout the manuscript, tables and supplemental documents. Cases P30, P34 and P35 were obtained from other laboratories and are represented in bold font.