NLGN2 – Schizophrenia

NLGN2 is a critical post‐synaptic cell adhesion molecule that plays an essential role in inhibitory synapse formation and maintenance. Multiple independent studies have implicated NLGN2 variants in the pathogenesis of schizophrenia (PMID:21551456), supporting its role in disrupting the excitatory–inhibitory balance within neural circuits. The evidence base includes rare, heterozygous, and de novo variants that perturb protein function, leading to synaptic deficits that are consistent with the neurobiology of schizophrenia.

Genetic evidence for NLGN2 in schizophrenia is robust. A de novo nonsense variant, c.441C>A (p.Tyr147Ter), was reported in a patient exhibiting neuropsychiatric symptoms, and additional rare missense variants, such as c.644G>A (p.Arg215His), were identified in case–control sequencing studies (PMID:27865048; PMID:21551456). Although segregation data are limited with no extensive familial co-segregation reported, the recurrence of disruptive variants across unrelated probands strengthens the genetic evidence.

The inheritance mode for these pathogenic variants appears to be autosomal dominant, as evidenced by the heterozygous and de novo occurrences. The variant spectrum includes a spectrum of loss‐of‑function mutations, with the reported nonsense variant c.441C>A (p.Tyr147Ter) serving as a prime example. This collective genetic burden underscores the contribution of NLGN2 abnormalities to schizophrenia, even in the context of potential incomplete penetrance noted in some familial observations.

Complementary functional studies further substantiate the genetic findings. In vitro and in vivo assays demonstrate that NLGN2 variants disrupt GABAergic synaptogenesis, leading to impaired inhibitory neurotransmission. Mouse models harboring analogous mutations exhibit behavioral abnormalities such as increased anxiety, impaired prepulse inhibition, and deficits in spatial learning and memory (PMID:29230184; PMID:26142252; PMID:29859117). These experimental observations provide a mechanistic link between molecular defects and the clinical phenotype of schizophrenia.

Integrating the genetic and functional evidence, the association between NLGN2 disruption and schizophrenia is compelling. The convergence of de novo and rare inherited variants, alongside consistent functional deficits in synaptic signaling, supports a strong clinical validity for this gene–disease relationship. Although additional studies may further refine the penetrance and expressivity of these variants, the existing data significantly informs diagnostic decision‑making and potential therapeutic strategies.

Key take‑home: Disruptions in NLGN2, as evidenced by both loss‑of‑function mutations and supportive functional models, represent a strong marker for schizophrenia and hold promising clinical utility for future diagnostic and treatment paradigms.

References

• Human Molecular Genetics • 2011 • Identification and functional characterization of rare mutations of the neuroligin-2 gene (NLGN2) associated with schizophrenia PMID:21551456
• American Journal of Medical Genetics Part A • 2017 • Neuroligin 2 nonsense variant associated with anxiety, autism, intellectual disability, hyperphagia, and obesity PMID:27865048
• Frontiers in Psychiatry • 2017 • Neuroligin 2 R215H Mutant Mice Manifest Anxiety, Increased Prepulse Inhibition, and Impaired Spatial Learning and Memory PMID:29230184
• Neuropharmacology • 2016 • Neuroligin 2 deletion alters inhibitory synapse function and anxiety-associated neuronal activation in the amygdala PMID:26142252
• Molecular Brain • 2018 • GABAergic deficits and schizophrenia-like behaviors in a mouse model carrying patient-derived neuroligin-2 R215H mutation PMID:29859117

Evidence Based Scoring (AI generated)