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 b isoform of neurexin 1, manifested increased head size and a high frequency of seizure disorder (88%) when compared with N-terminal deletions of NRXN1.

Structural Genome Variations Related to Craniosynostosis

“…Intragenic deletions of CNTNAP2 , IMMP2L , MCPH1 , and NRXN1 have been found in patients with intellectual disability, speech delay, autism spectrum disorders, hypotonia, Gilles de la Tourette syndrome, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, Pitt-Hopkins syndrome, stuttering, attention deficit hyperactivity disorder, and schizophrenia [van Daalen et al, 2011;Schaaf et al, 2012;Poot, 2015Poot, , 2017. Engineered forms of the CNTNAP2 encoded Caspr2 containing internal deletions proved to be defective in oligomerization and thus exerted a dominant negative effect [Canali et al, 2018].…”

Dual genetic diagnoses: Atypical hand‐foot‐genital syndrome and developmental delay due to de novo mutations in HOXA13 and NRXN1

“…Haploinsufficiency of NRXN1 due to whole gene or exonic deletion has been associated with a spectrum of neuropsychiatric and developmental disorders, including autistic spectrum disorder (ASD), intellectual impairment, hypotonia and motor developmental delay, language delay, epilepsy, schizophrenia, and minor dysmorphic features [Ching et al, 2010;Schaaf et al, 2012;B ena et al, 2013;Dabell et al, 2013]. Neurexin deletions show incomplete penetrance and may be found in healthy individuals [Ching et al, 2010;Schaaf et al, 2012;B ena et al, 2013;Dabell et al, 2013]. Significant urogenital or limb anomalies do not appear to have been reported before in association with NRXN1 deletions and are most likely accounted for by the presence of the HOXA13 mutation in this patient.…”

“…The neurexin 1 (NRXN1) gene has two independent promoters generating two major isoforms, neurexin 1-a and neurexin 1-b. Deletions involving NRXN1 are associated with a wide spectrum of neuropsychiatric disorders, including developmental delay (particularly speech), autism, schizophrenia and mild dysmorphic features; but they have not been associated with limb or urogenital anomalies [Ching et al, 2010;Schaaf et al, 2012;B ena et al, 2013;Dabell et al, 2013].…”

The complex genetics in autism spectrum disorders

“…Multiple genetic changes in Nrxn [84][85][86][87][88][89][90][91][92][93][94] and Nlgn genes [92,93,[95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110] have been found in ASD patients. These changes include (i) point mutations, which cause frame shifts, small deletions, and missense mutations in both coding and promoter regions, (ii) distinct translocation events, and (iii) large-scale deletions of chromosomal DNA containing these gene loci.…”