NRXN2 Homozygous Variant Identified in a Family with Global Developmental Delay, Severe Intellectual Disability, EEG Abnormalities and Speech Delay: A new Syndrome?

Background. This study aims to characterize the clinical phenotype of a family with two siblings exhibiting neurological manifestations, utilizing whole exome sequencing (WES) to identify potential pathogenic variants within the NRXN2 gene. Methods. A consanguineous family with two affected siblings displaying developmental delay, severe intellectual disability, epilepsy, and speech delay was examined. WES was performed on DNA samples from affected and unaffected family members, followed by a comprehensive bioinformatics analysis. In-silico tools were employed for variant interpretation and structural modeling of the NRXN2 protein. Clinical and genetic data were integrated to elucidate the potential impact of the identified variant. Results. WES revealed a novel homozygous missense variant (c.1475T>G, p.Leu492Arg) in the NRXN2 gene in both affected siblings. This variant was absent in healthy family members and public databases. In-silico analysis predicted a detrimental effect on protein function. Parental segregation confirmed heterozygous carrier status. The variant was classified as 'Likely Pathogenic' based on ACMG/AMP criteria. Conclusion. This study identifies a novel homozygous missense variant in NRXN2 associated with global developmental delay, severe intellectual disability, speech delay and epilepsy. The findings underscore the critical role of NRXN2 in neurodevelopment and highlight the potential implications of genetic variations within this gene in neurodevelopmental disorders. Further research and functional validation are warranted to deepen our understanding of NRXN2-related disorders and explore potential therapeutic interventions.