Variant Synonymizer: Platform to identify mutations defined in different ways is available now!

VarSy

Over 2,000 gene–disease validation summaries are now available—no login required!

Browse Summaries

NRXN2 – Autism Spectrum Disorder

Heterozygous disruptions of NRXN2 have been reported in three unrelated individuals with autism spectrum disorder (ASD), supporting a role for NRXN2 haploinsufficiency in disease pathogenesis. A de novo 921 kb microdeletion at 11q13.1 encompassing NRXN2 was identified in a boy with global developmental delay and significant language delay but without autistic behaviors, contrasting with two earlier patients who exhibited ASD features (PMID:29654904). In a resequencing cohort of 142 ASD probands, a truncating NRXN2 variant was found in one patient, inherited from a father with severe language delay and family history of schizophrenia, suggesting incomplete penetrance and autosomal dominant inheritance with variable expressivity (PMID:21424692).

Functional studies in mice provide concordant evidence: Nrxn2α knockout mice display core autism-related behaviors including sociability deficits, social memory impairments, and anxiety-like phenotypes, along with decreased excitatory synaptic transmission and altered NMDAR function (PMID:25423136; PMID:25745399). These data support a haploinsufficiency mechanism, though the incomplete penetrance observed in humans indicates additional modifiers influence clinical outcomes. Key take-home: Heterozygous NRXN2 loss-of-function variants confer moderate risk for ASD under an autosomal dominant model, with functional models validating synaptic deficits and behavioral phenotypes.

References

  • European Journal of Medical Genetics • 2018 • A de novo 921 Kb microdeletion at 11q13.1 including neurexin 2 in a boy with developmental delay, deficits in speech and language without autistic behavior PMID:29654904
  • Human Genetics • 2011 • Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia PMID:21424692
  • Translational Psychiatry • 2014 • Deletion of α-neurexin II results in autism-related behaviors in mice PMID:25423136
  • Frontiers in Synaptic Neuroscience • 2015 • Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors PMID:25745399

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Three unrelated probands with heterozygous NRXN2 loss-of-function variants support a role in ASD but with incomplete penetrance ([PMID:29654904]; [PMID:21424692])

Genetic Evidence

Limited

Identification of a de novo microdeletion and a familial truncating mutation in NRXN2 across three ASD probands

Functional Evidence

Moderate

Two independent Nrxn2α knockout mouse models recapitulate ASD-like social deficits and synaptic transmission abnormalities ([PMID:25423136]; [PMID:25745399])