Intrafamilial Variability in NRXN1-Associated Neurodevelopmental Disorders: Clinical and Genetic Insights from a...

The neurexin1 gene (NRXN1) encodes a presynaptic adhesion molecule that plays a critical role in synapse formation, maintenance, and function. Copy-number variants (CNVs) affecting the NRXN1 locus, including submicroscopic deletions, represent rare variant acting as a predisposition for neurodevelopmental disorders, such as Pitt-Hopkins-like syndrome type 2 (MIM #614325) and susceptibility to schizophrenia (MIM #621407). Variations in NRXN1 gene are associated with marked clinical heterogeneity. We present a familial case involving two male siblings (aged 6 and 5 years) and their 28-year-old mother, all exhibiting variable neurodevelopmental phenotypes. Both children demonstrated disharmonic developmental profiles characterized by impaired communication, speech largely intelligible only to their parents, and behaviors consistent with autism spectrum disorder, including reduced eye contact. Mother represents a carrier with only subtle, nonspecific behavioral traits, further supporting the concept of incomplete penetrance and variable expressivity associated with this genetic alteration. Genetic analysis identified a 317 kb NRXN1 deletion shared by all affected family members, accompanied by significant intrafamilial phenotypic variability, suggesting the contribution of additional genetic and/or modifying factors. These findings support the concept that NRXN1 deletions alone do not determine clinical outcome but rather act within a broader genetic and biological context. The marked intrafamilial phenotypic variability and incomplete penetrance observed in this family is compatible with a multiple-hit model, whereby NRXN1 deletions act as susceptibility factors whose phenotypic consequences are shaped by additional genetic and modifying influences. However, the genetic mechanisms underlying the observed phenotypic variability warrant further investigation.