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

Abstract

BackgroundMicrodeletions 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.ResultsIn the present study we performed array CGH analysis on 10,397 individuals referred for diagnostic cytogenetic analysis, using a custom oligonucleotide array, which included 215 NRXN1 probes (median spacing 4.9 kb). We found 34 NRXN1 deletions (0.33% of referrals) ranging from 9 to 942 kb in size, of which 18 were exonic (0.17%). Three deletions affected exons also in the beta isoform of NRXN1. No duplications were found. Patients had a range of phenotypes including developmental delay, learning difficulties, attention deficit hyperactivity disorder (ADHD), autism, speech delay, social communication difficulties, epilepsy, behaviour problems and microcephaly. Five patients who had deletions in NRXN1 had a second CNV implicated in neurodevelopmental disorder: a CNTNAP2 and CSMD3 deletion in patients with exonic NRXN1 deletions, and a Williams-Beuren syndrome deletion and two 22q11.2 duplications in patients with intronic NRXN1 deletions.ConclusionsExonic deletions in the NRXN1 gene, predominantly affecting the alpha isoform, were found in patients with a range of neurodevelopmental disorders referred for diagnostic cytogenetic analysis. The targeting of dense oligonucleotide probes to the NRXN1 locus on array comparative hybridisation platforms provides detailed characterisation of deletions in this gene, and is likely to add to understanding of the importance of NRXN1 in neural development.

Phenotypic spectrum of NRXN1 mono‐ and bi‐allelic deficiency: A systematic review

“…17,24 As expected for many of the above-mentioned neurodevelopmental phenotypes, delays in receptive and/or expressive language development have been consistently reported in children with NRXN1 deletions. 13,17,21,23,56 Brignell et al 74 made a comprehensive evaluation of speech and language phenotypes, reporting speech difficulties in 69% of the patients with NRXN1 deletions.…”

Characterization of speech and language phenotype in children with NRXN1 deletions

“…Heterozygous exonic deletions of NRXN1 have been associated with a range of neurodevelopmental and neuropsychiatric phenotypes (Bucan et al, ; Ching et al, ; Curran, Ahn, Grayton, Collier, & Ogilvie, ; Gregor et al, ; Onay et al, ; Rujescu et al, ; Vinas‐Jornet et al, ; Wang & Gong, ; Zweier, ) and are found in about 1 in 500 samples referred for clinical microarray analysis. However, NRXN1 deletions are frequently inherited from a mildly affected or clinically unaffected parent, and are also found in control populations at a frequency of about 1 in 5,000, indicating incomplete penetrance (Ching et al, ; Lowther et al, ; Schaaf et al, ).…”

“…Speech and language difficulties are expected to be present in many of the above‐mentioned neurodevelopmental phenotypes, and delays in speech and/or language have been reported consistently in children with NRXN1 deletions (Bena et al, ; Ching et al, ; Curran et al, ; Dabell et al, ; Gregor et al, ), yet comprehensive evaluation of speech and language phenotypes has not been reported in these children. Here, we describe the communication phenotypes in 21 children with exonic deletions of NRXN1 , including evaluation of speech production (phonology, articulation, dysarthria, childhood apraxia of speech), oromotor structure and function, receptive and expressive language and pragmatic (social) language ability.…”

BBGRE: brain and body genetic resource exchange

“…Using the BBGRE tool, we found exonic deletions in the NRXN1 gene, predominantly affecting the alpha isoform, in patients with a range of neurodevelopmental disorders referred for diagnostic cytogenetic analysis (12). Patients have a range of phenotypes including developmental delay, learning difficulties, attention-deficit hyperactivity disorder, autism, speech delay, social communication difficulties, epilepsy, behaviour problems and microcephaly.…”