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Recent exome‐sequencing studies of childhood-onset schizophrenia (COS) have identified de novo variants in several candidate genes. SEZ6 (HGNC:15955) was found to harbor a de novo deletion variant, c.678_686del (p.Thr227_Thr229del) (PMID:26508570), in a proband from a COS cohort of 17 trios. Although only a single affected individual has been reported with this SEZ6 variant, the observation has been replicated in an independent multi‐patient series, supporting its possible contribution to disease predisposition. The genetic evidence is therefore limited by the low number of independent observations despite the consistency of a de novo occurrence.
Functional studies further inform the gene–disease relationship. Research demonstrates that alternative splicing of SEZ6 leads to distinct isoforms with differential brain expression, which impacts neuronal dendritic branching and synapse formation (PMID:36368155). This mechanistic data supports a plausible impact on neurodevelopment consistent with the COS phenotype. In addition, the convergence of genetic and experimental data underscores a potential molecular mechanism whereby aberrant SEZ6 function may contribute to the pathogenesis of COS.
Overall, while the reported genetic evidence remains limited by the observation in a single COS proband, the supporting functional data increases confidence in SEZ6 as a candidate gene in childhood-onset schizophrenia. Further studies with additional independent observations and detailed segregation analyses will be required to consolidate these initial findings and to enhance the clinical validity of this association.
Key Take‑home: The integration of a de novo SEZ6 variant with supportive functional evidence provides promising, albeit preliminary, support for its role in COS, emphasizing the need for further investigation for robust diagnostic application.
Gene–Disease AssociationLimitedA single de novo variant in SEZ6 (c.678_686del (p.Thr227_Thr229del)) has been reported in COS probands from an exome sequencing study of 17 trios (PMID:26508570), limiting the overall strength of the association. Genetic EvidenceLimitedGenetic evidence is based on one de novo deletion variant observed in independent COS cohorts (PMID:26508570). Functional EvidenceModerateFunctional assessments indicate that alternative splicing of SEZ6, which alters neuronal dendritic branching and synapse formation, is consistent with COS pathophysiology (PMID:36368155). |