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NRXN3 – Autism

Rare heterozygous loss-of-function events in NRXN3 have been implicated in autism spectrum disorder through limited family and sporadic case studies. In a three-generation Chinese pedigree, a rare exonic deletion in the NRXN3 alpha isoform co-segregated with autism, moderate intellectual disability (HP:0002342), attention-deficit hyperactivity disorder (HP:0007018), and variable neuropsychiatric features across three affected carriers ([PMID:30076746]). A literature compilation of 23 sporadic deletion cases revealed autism features in 9 individuals (39%) ([PMID:30076746]).

Further support comes from a heterozygous frameshift variant c.159_160del (p.Phe53LeufsTer16) in the NRXN3 beta isoform identified in a 5-year-old girl with autism spectrum disorder and developmental delay; this variant was inherited from an unaffected mother, consistent with incomplete penetrance of NRXN3 haploinsufficiency ([PMID:37372397]). Functional assays to date demonstrate complex splicing and synaptic localization of neurexin-3 but lack autism-specific mechanistic studies.

These data meet a Limited level of clinical validity for NRXN3 in autism due to small cohort sizes, incomplete penetrance, and absence of replication in large independent studies. Further large-scale genetic screening and targeted functional assays are needed to establish NRXN3 as a diagnostic marker for ASD.

Key Take-home: NRXN3 haploinsufficiency shows preliminary evidence for an autosomal dominant contribution to autism with incomplete penetrance, but current data remain limited for routine clinical application.

References

  • American journal of medical genetics. Part B, Neuropsychiatric genetics • 2018 • A rare exonic NRXN3 deletion segregating with neurodevelopmental and neuropsychiatric conditions in a three-generation Chinese family. PMID:30076746
  • Genes • 2023 • Case Report-An Inherited Loss-of-Function NRXN3 Variant Potentially Causes a Neurodevelopmental Disorder with Autism Consistent with Previously Described 14q24.3-31.1 Deletions. PMID:37372397

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single multiplex pedigree with three carriers co-segregating an NRXN3 exonic deletion; 9/23 sporadic deletion cases with autism features; limited cohort size and replication

Genetic Evidence

Limited

One family with segregation in 3 individuals; additional sporadic deletion cases (9/23) with autism features; one inherited frameshift variant described

Functional Evidence

Limited

Expression and splicing studies demonstrate synaptic role of NRXN3, but no direct autism-specific functional assays