NRXN2

Inheritance Pattern: AD

Disease ID:MONDO:0005260

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*NRXN2* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2011 (Gauthier et al., PMID: 21424692). Since the initial report of a frameshift variant in an individual with autism that was shown to lead to loss of function *in vitro* (PMID: 21424692), only five other truncating variants have been reported in individuals with neurodevelopmental disorders. The phenotype information is very limited. Five variants were identified in cohort sequencing studies of autism spectrum disorder (ASD), and no clinical information was provided (PMIDs: 21424692, 30392784, 31398340, 31981491). Another variant was identified in a child with global developmental delay and syndromic features, including microcephaly and congenital heart defect (PMID: 37120078). Six frameshift variants that have been reported in six probands in five publications (PMIDs: 21424692, 30392784, 31398340, 31981491, 37120078) are included in this curation. Two occurred *de novo*, two were paternally inherited, and two were of unknown inheritance. In one family, the heterozygous father had a history of severe language delay (PMID: 21424692). In another family, the paternally inherited variant was present in two brothers with ASD but not in their sister, who was also diagnosed with ASD (PMID: 31398340). *NRXN2* truncating variants have also been reported in a control subject in an autism exome study (PMID: 31981491), an unaffected parent of a child with autism (PMID: 35982159), and in 10 schizophrenia cases and 9 controls (PMID: 35396579). In addition, *de novo* missense variants in *NRXN2* have been observed in individuals with developmental disorders (PMID: 33057194) and ASD (PMIDs: 35982159, 36368308). However, because there is no experimental evidence of gene impact for any of these variants, they were not scored. *NRXN2* is highly constrained for truncating variants (pLI = 1, LOEUF = 0.32, gnomAD v4.1.0) and also exhibits constraint for missense variants (Z score = 3.1). Of note, no single gene deletions affecting *NRXN2* were identified. Deletions involving other genes in addition to *NRXN2* were not counted as evidence because the contribution of the other genes cannot be ruled out. The mechanism of pathogenicity appears to be loss of function, based on the few reported variants, but no functional studies have been performed. This gene-disease relationship is also supported by experimental evidence, including biochemical function, protein interactions, and mouse models. Neurexins are presynaptic cell adhesion molecules that bind to postsynaptic ligands, such as neuroligins. They mediate signaling across the synapse and shape the properties of neural circuits by specifying synaptic functions. There are three *NRXN* genes (*NRXN1*, *NRXN2*, and *NRXN3*) that each produce longer α-NRXN and shorter β-NRXN isoforms. Heterozygous deletions in *NRXN1* cause complex neurodevelopmental disorder with reduced penetrance and variable expressivity, and are also enriched in schizophrenia and attention deficit-hyperactivity disorder. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 15, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0005260

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: Ambry Genetics