NRXN1 – Autism Spectrum Disorder

Neurexin 1 (NRXN1) haploinsufficiency is strongly associated with autism spectrum disorder (ASD). Heterozygous exonic deletions of NRXN1 occur at a significantly higher rate in ASD cohorts compared to controls (PMID:20468056). Phenotypes include ASD, language delays, and intellectual disability, with evidence of co-segregation in multiple families.

Genetic Evidence

NRXN1-related ASD follows an autosomal dominant pattern with incomplete penetrance. In a clinical CGH screen of 3,540 individuals, 12 subjects harbored NRXN1 exonic deletions, and three families showed segregation of the deletion with ASD or intellectual disability (PMID:20468056). De novo and inherited deletions disrupt alpha-NRXN1 exons and promoter regions, consistent with loss-of-function. A truncating point mutation, c.2386G>T (p.Glu796Ter), was identified in siblings with biallelic deletions and severe ASD (PMID:25149956).

Functional Evidence

Conditional heterozygous NRXN1 deletion in human ESC-derived neurons impairs synaptic transmission without affecting synapse number, indicating a direct role in neurotransmitter release (PMID:26279266). In forebrain neuron cultures, activity-dependent alternative splicing of NRXN1, regulated by SAM68, modulates synapse assembly, supporting a splicing-based mechanism of dysfunction (PMID:22196734). Rare start-codon mutations in the NRXN1β transcript (c.3G>A (p.Met1Ile)) reduce protein levels at synapses in vitro (PMID:24064682).

Conflicting Evidence

Sequencing of 313 Chinese ASD patients identified multiple missense and synonymous NRXN1 variants without significant enrichment versus controls, suggesting that not all rare NRXN1 variants confer ASD risk (PMID:22405623).

Integration & Conclusion

Collectively, >12 unrelated ASD probands with LoF CNVs, segregation in three families, and concordant functional defects in neuronal models justify a Strong clinical validity classification. Haploinsufficiency via CNVs or truncating point mutations disrupts synaptic function, while splicing variation adds mechanistic nuance. Additional de novo and inherited variants likely contribute to phenotypic heterogeneity and incomplete penetrance (PMID:22337556).

Key Take-home: NRXN1 loss-of-function variants are a strong genetic risk factor for ASD, warranting first-tier CNV and targeted sequencing in diagnostic work-ups.

References

• American journal of medical genetics. Part B, Neuropsychiatric genetics • 2010 • Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. PMID:20468056
• American journal of medical genetics. Part A • 2012 • Mutations in NRXN1 in a family multiply affected with brain disorders: NRXN1 mutations and brain disorders. PMID:22337556
• Cell stem cell • 2015 • Human Neuropsychiatric Disease Modeling using Conditional Deletion Reveals Synaptic Transmission Defects Caused by Heterozygous Mutations in NRXN1. PMID:26279266
• Cell • 2011 • SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1. PMID:22196734
• Psychiatric genetics • 2013 • Rare variants analysis of neurexin-1β in autism reveals a novel start codon mutation affecting protein levels at synapses. PMID:24064682
• Journal of psychiatric research • 2012 • Mutation analysis of the NRXN1 gene in a Chinese autism cohort. PMID:22405623
• Seminars in pediatric neurology • 2014 • Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis. PMID:25149956

Evidence Based Scoring (AI generated)