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

Abstract

Neurexins are presynaptic cell adhesion molecules critically involved in synaptogenesis and vesicular neurotransmitter release. They are encoded by three genes (NRXN1-3), each yielding a longer alpha (α) and a shorter beta (β) transcript. Deletions spanning the promoter and the initial exons of the NRXN1 gene, located in chromosome 2p16.3, are associated with a variety of neurodevelopmental, psychiatric, neurological and neuropsychological phenotypes. We have performed a systematic review to define (a) the clinical phenotypes most associated with monoallelic exonic NRXN1 deletions, and (b) the phenotypic features of NRXN1 bi-allelic deficiency due to compound heterozygous deletions/mutations. Clinically, three major conclusions can be drawn: (a) incomplete penetrance and pleiotropy do not allow reliable predictions of clinical outcome following prenatal detection of mono-allelic exonic NRXN1 deletions. Newborn carriers should undergo periodic neuro-behavioral observations for the timely detection of warning signs and the prescription of early behavioral intervention; (b) the presence of additional independent genetic risk factors should always be sought, as they may influence prognosis; (c) children with exonic NRXN1 deletions displaying early-onset, severe psychomotor delay in the context of a Pitt-Hopkins-like syndrome 2 phenotype, should undergo DNA sequencing of the spared NRXN1 allele in search for mutations or very small insertions/deletions. K E Y W O R D S autism spectrum disorder, compound heterozygosity, developmental delay, neurexin 1, Pitt-Hopkins-like syndrome 2, schizophrenia

Cross-Platform Validation of Neurotransmitter Release Impairments in Schizophrenia Patient-DerivedNRXN1-Mutant Neurons

“…Mutations associated with neuropsychiatric disorders often predispose to multiple disease conditions. For example, NRXN1 CNVs are among the most frequent mutations associated with not only schizophrenia, but also intellectual disability, autism-spectrum disorders, epilepsy and others (Castronovo et al, 2020; Lowther et al, 2017, Kasem et al, 2018; Szatmari et al, 2007; Guilmatre et al, 2009; Liu et al, 2012; Ching et al, 2010; Nag et al, 2013; Huang et al, 2017). We thus decided to test whether the similarity of the synaptic impairments we observed in NRXN1 del neurons generated from schizophrenia patient-derived iPS cells to those we previously described for NRXN1 -deficient neurons generated from ES cells can be validated with neurons generated from iPS cells carrying a newly engineered conditional NRXN1 mutation.…”

“…A large number of 2p16.3 CNVs were described that cause different deletions of chromosomal DNA, but affect expression of only a single gene, NRXN1 (Marshall et al, 2017, Castronovo et al, 2020). These CNVs strongly predispose to schizophrenia.…”

“…As a result, NRXN1 CNVs are at present the most prevalent known single-gene mutation associated with schizophrenia, although other CNVs involving multiple genes (such as 22q11.2) are more prevalent among schizophrenia patients (Marshall et al, 2017; Hu et al, 2019; Kasem et al, 2018). In addition, NRXN1 del CNVs predispose to other neuropsychiatric and neurodevelopmental disorders (Lowther et al, 2017, Castronovo et al, 2020). Strikingly, our previous study suggested that heterozygous deletions of NRXN1 in human but not in mouse neurons cause a distinct and robust impairment in neurotransmitter release without changing the development or the morphology of neurons (Pak et al, 2015).…”

“…Of these CNVs, 16p11.2 and 22q11.2 CNVs affect more than 20 genes, whereas 2p16.3 CNVs impact only one or more exons of a single gene, NRXN1 , which encodes the presynaptic cell-adhesion molecule neurexin-1 (Hu et al, 2019; Coelewij and Curtis, 2018; Kasem et al, 2018; Sudhof, 2017; Kirov, 2015; Marshall et al, 2017). NRXN1 CNVs confer an approximately ten-fold increase in risk of schizophrenia, and additionally strongly predispose to other neuropsychiatric disorders, especially autism and Tourette syndrome (Lowther et al, 2017, Castronovo et al, 2020). Moreover, genome-wide association studies using DNA microarrays identified common changes in many other genes that predispose to schizophrenia with smaller effect sizes (SCZ working group of PGC, 2014; Parnidas et al, 2018; Fromer et al, 2014; Fromer et al, 2016; Ripke et al, 2017; Sullivan and Geschwind 2019; Flaherty et al, 2019; Hall et al, 2020).…”

Further insight into the neurobehavioral pattern of children carrying the 2p16.3 heterozygous deletion involving NRXN1: Report of five new cases

“…The heterozygous deletions and intragenic mutations involving NRXN1 have been recently estimated to account for a small but relatively significant proportion of individuals with ID/GDD (0.18%), ASD (0.36%) and schizophrenia (0.16%) 5 . Despite the evidence supporting the contribution of heterozygous NRNX1 deletions to neuropsychiatric disorders, these genomic rearrangements have also been reported in population‐based databases (0.02%), and in apparently healthy parents [AHP], suggesting incomplete penetrance 1,3 …”