DGCR2 – Schizophrenia

The association between DGCR2 and schizophrenia is supported by multiple lines of evidence, including a de novo mutational finding in sporadic schizophrenia cases and corroborative gene expression and deletion syndrome studies. The initial exome sequencing study identified a potentially disruptive de novo mutation in DGCR2 in a cohort of 53 sporadic cases (PMID:21822266), suggesting that rare coding variants in DGCR2 may contribute to disease risk.

Overall, the clinical validity of the DGCR2‑schizophrenia association is assessed as Limited. This conclusion is based on the observation of a single de novo mutation in a well‐characterized study (PMID:21822266), with additional supporting evidence from gene expression analyses in different disease stages (PMID:30923314) and a review of the 22q11.2 deletion syndrome context (PMID:33098288).

Genetic evidence indicates an autosomal dominant mode of effect for deleterious DGCR2 variants, with no significant segregation data reported among affected relatives. A representative variant reported in the literature is c.445G>A (p.Gly149Asp), which underscores the rare and disruptive nature of such mutations in the context of schizophrenia genetics.

Experimental evidence further supports the putative role of DGCR2 in disease pathogenesis. Functional studies using in vivo mouse models have shown that knockdown of DGCR2 impairs radial migration and cortical lamination, likely via disruption of the Reelin signaling cascade (PMID:29305086). These results imply that haploinsufficiency of DGCR2 can perturb early corticogenesis, aligning well with the neurodevelopmental hypotheses underlying schizophrenia.

Some studies acknowledge that while DGCR2 is among several candidate genes in the 22q11.2 region, the low recurrence of identified variants calls for caution in overinterpreting its contribution in isolation. Nonetheless, the convergence of de novo mutational data, gene expression findings, and functional assays supports the gene’s involvement in disease etiology, albeit at a modest level of evidence.

In conclusion, although the genetic evidence for DGCR2’s role in schizophrenia remains limited due to the low number of definitive variant occurrences, the moderate level of functional evidence provides a biological rationale for its involvement. Key take‑home: DGCR2 constitutes a promising diagnostic marker with potential therapeutic implications, warranting further replication studies to solidify its clinical utility.

References

• Nature Genetics • 2011 • Exome sequencing supports a de novo mutational paradigm for schizophrenia PMID:21822266
• NPJ Schizophrenia • 2019 • Gene expression over the course of schizophrenia: from clinical high‑risk for psychosis to chronic stages PMID:30923314
• Acta Biochimica et Biophysica Sinica • 2020 • 22q11.2 deletion syndrome and schizophrenia PMID:33098288
• Biological Psychiatry • 2018 • The Candidate Schizophrenia Risk Gene DGCR2 Regulates Early Steps of Corticogenesis PMID:29305086

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