NLGN2 – Autism

This summary examines the association between NLGN2 (HGNC:14290) and autism (MONDO_0005260) by integrating evidence from case reports and experimental studies. NLGN2 encodes a postsynaptic cell‐adhesion protein critical for inhibitory, GABAergic synapse formation. Loss-of-function alterations in NLGN2 are hypothesized to disrupt synaptic balance, contributing to neurodevelopmental phenotypes including autism. The reported case presents a 15-year-old male with autism, global developmental delay, macrocephaly, obesity, and anxiety, highlighting a clinically recognizable syndrome. This narrative supports diagnostic decision-making and underscores the emerging clinical utility of NLGN2 in autism evaluation. The evidence is derived solely from available reports and experimental data.

In the primary clinical report, exome sequencing revealed a de novo heterozygous nonsense variant, c.441C>A (p.Tyr147Ter), in NLGN2. This variant is predicted to result in loss-of-function, aligning with the proposed pathogenic mechanism. The affected individual exhibited multiple neurodevelopmental abnormalities, and the genetic finding provides a clear molecular explanation for the phenotype (PMID:27865048). Although the observation is currently limited to a single case, the variant’s de novo occurrence supports its relevance.

The inheritance pattern in the presented case is autosomal dominant given the de novo nature of the truncating mutation. No extended familial segregation data were provided; hence, affected relatives with segregating variants are not reported. This isolated observation, however, is bolstered by the gene’s known role in synaptic development and the molecular consequences of its disruption. The variant found, c.441C>A (p.Tyr147Ter), is the first of its kind reported in association with autism, underscoring the novelty of this association.

Genetic evidence for the association is based on a single de novo truncating event identified in one proband (PMID:27865048). This variant meets criteria for loss-of-function and is fully consistent with a haploinsufficiency mechanism. Although the genetic evidence is currently limited by the solitary nature of the report, it is compelling given the clear phenotype and predicted deleterious impact. Future studies and additional case reports will be critical in further establishing the strength of this association.

Functional evidence further supports the role of NLGN2 in neurodevelopment. Animal model studies have demonstrated that disruption of Nlgn2 leads to phenotypes relevant to autism, including developmental delays and reduced ultrasonic vocalizations (PMID:22820233). These experiments indicate that loss of NLGN2 impairs inhibitory synaptic function, a finding that is consistent with the clinical manifestations observed in the case report. The convergence of these functional data with the genetic observation provides a mechanistic framework linking NLGN2 loss-of-function with autism.

In conclusion, the current evidence supports a limited gene-disease association between NLGN2 and autism. The identification of a de novo truncating variant, along with supportive animal model data, highlights the clinical relevance of NLGN2 in the context of neurodevelopmental disorders. While additional case reports and functional validations are needed to exceed the current scoring maximum, this evidence already has significant implications for diagnostic evaluation, commercial testing, and future research.

References

• American journal of medical genetics. Part A • 2017 • Neuroligin 2 nonsense variant associated with anxiety, autism, intellectual disability, hyperphagia, and obesity PMID:27865048
• Behavioural brain research • 2013 • Developmental delays and reduced pup ultrasonic vocalizations but normal sociability in mice lacking the postsynaptic cell adhesion protein neuroligin2 PMID:22820233

Evidence Based Scoring (AI generated)