Clinical phenotypic spectrum of NRXN1 microdeletions and their association with epilepsy: A systematic review and meta‐analysis

Abstract Objective NRXN1 microdeletions are associated with an increased genetic risk for various neuropsychiatric disorders, with diverse breakpoints complicating research, diagnosis, and treatment. This study aims to investigate the deletion rate and penetrance of NRXN1 microdeletions across different clinical phenotypes through meta‐analysis while exploring their relationship with epilepsy and summarizing the characteristics of NRXN1 biallelic variations. Methods For meta‐analysis, a systematic review of published studies was conducted to calculate NRXN1 microdeletion rates and penetrance across different disorders, with comparisons to control groups. For systematic review, data from 401 cases across 57 studies were analyzed to compare microdeletion characteristics in patients with and without epilepsy, alongside a review of NRXN1 biallelic variation clinical features. Results NRXN1 microdeletion carriers had a 3.20‐fold higher disease risk compared to noncarriers. The deletion rate was elevated in patients with autism, schizophrenia, and Tourette syndrome relative to controls. Additionally, NRXN1 microdeletions were more prevalent in epilepsy patients with comorbidities than in those with epilepsy alone. Among epilepsy patients, 81.3% had comorbidities. Deletions involving exons 1–6 were more frequent in patients with epilepsy, of whom 71.42% were diagnosed with genetic generalized epilepsy (GGE). Among those with NRXN1 biallelic variations, 53.84% had epilepsy, and all experienced generalized seizures. Significance Understanding genotype–phenotype associations in NRXN1 microdeletion‐related diseases is critical for early diagnosis and management. Our study shows that NRXN1 microdeletions have been associated with various neuropsychiatric disorders and exhibit incomplete penetrance. In epilepsy, patients with NRXN1 microdeletions are associated with mental comorbidities and generalized seizure types, particularly involving exon 1–6 deletions, and are common in patients with GGE.