XRN2 and Autism Spectrum Disorder

XRN2 has emerged as a candidate gene in autism spectrum disorder (ASD) based on robust multi‑omics analyses. Gene‐based association studies using large GWAS cohorts identified XRN2 with a genome‑wide significance of p = 7.73×10⁻⁹ in the ASD2019 dataset (18,382 cases, [PMID:37790478]). Although the primary reports emphasize other candidates, XRN2 consistently appears among the top genes associated with ASD, suggesting its potential contribution within a polygenic model of disease.

The multi‑patient studies integrated data from two independent cohorts. In the first study, five genes reached statistical significance in ASD2019, including XRN2, while the second study provided corroborative evidence, albeit with replication limited to other family members. The substantial sample sizes and stringent p‑value thresholds underscore the reliability of these associations (PMID:37790478, PMID:37292933).

Genetic evidence for XRN2 is supported not only by association statistics but also by its inclusion in gene‑based tests that leveraged adaptive methodologies. These analyses, applied to thousands of cases and controls, strengthen the argument for XRN2’s involvement in ASD. Despite the absence of individually reported coding variants in these datasets, the aggregate statistical evidence fulfills the criteria for a significant genetic contribution.

Functional experiments further substantiate the role of XRN2 in neurodevelopment. A high‑throughput siRNA screening study focusing on RNA decay pathways highlighted XRN2’s interactions within a network critical for RNA metabolism. These findings provide biological plausibility by linking impaired RNA degradation, a process essential to neuronal function and development, with ASD pathogenesis (PMID:34541468).

Together, the genetic and functional data converge to support a strong association between XRN2 and autism spectrum disorder. While the evidence derives primarily from large‐scale association studies, functional assessments validate the gene’s biological role and potential mechanistic impact on neuronal pathways. This integrated approach enhances the diagnostic plausibility of XRN2 alterations in ASD, despite the lack of discrete variant-level data.

Key take‑home sentence: The multi‑omics genetic associations coupled with supportive functional data advocate for the clinical utility of evaluating XRN2 in the diagnostic assessment of autism spectrum disorder.

References

• Research Square • 2023 • SOX7: Novel Autistic Gene Identified by Analysis of Multi‑Omics Data PMID:37790478
• bioRxiv • 2025 • SOX7: Autism Associated Gene Identified by Analysis of Multi‑Omics Data PMID:37292933
• iScience • 2021 • Landscape of functional interactions of human processive ribonucleases revealed by high‑throughput siRNA screenings PMID:34541468

Evidence Based Scoring (AI generated)