SEZ6L2 and Autism

This summary evaluates the association between SEZ6L2 (HGNC:30844) and autism (MONDO_0005260) based on available case‐based, multi‐patient, and functional studies. The evidence originates from several sources that have interrogated the role of SEZ6L2 in neurodevelopmental phenotypes, with special attention to autism.

In a multi‐patient study, coding variants in SEZ6L2 were examined in a large cohort. A notable finding was a significant association between autism and a coding variant (12/1106 autism probands vs. 3/1161 controls [PMID:19242545]), suggesting that variation in SEZ6L2 might influence autism risk. However, the study also noted that association could not be replicated independently.

Case report evidence from a separate cohort investigating 16p11.2 rearrangements included no identified mutations in SEZ6L2 despite examining multiple candidate genes ([PMID:20503337]). The absence of segregating variants within the affected family members and the negative sequencing results further cloud the genetic contribution of SEZ6L2 in individual case studies.

Functional evidence supporting the potential involvement of SEZ6L2 in autism comes from expression analyses. Investigations demonstrated that SEZ6L2 expression in human fetal brain—being highest in post‐mitotic cortical layers, hippocampus, amygdala, and thalamus—underscores its relevance to neurodevelopment ([PMID:19242545]). Additionally, systematic proteomic analysis identified SEZ6L2 as a substrate of BACE enzymes, linking it mechanistically to pathways that may impact neural function ([PMID:23430253]).

Overall, the genetic data, though suggestive with one coding variant association, remain limited primarily because of the modest variant counts, lack of robust segregation evidence, and failure to replicate in independent cohorts. The functional studies offer supplementary context by highlighting SEZ6L2’s neurodevelopmental expression and its biochemical interactions, yet they do not unequivocally establish a pathogenic mechanism related to autism.

Key take‑home: While current studies implicate SEZ6L2 as a potential risk factor for autism, further large‐scale replication and functional validation are needed before it can be fully integrated into clinical diagnostic and therapeutic frameworks.

References

• American journal of medical genetics. Part A • 2010 • Duplication 16p11.2 in a child with infantile seizure disorder PMID:20503337
• PloS one • 2009 • Association and mutation analyses of 16p11.2 autism candidate genes PMID:19242545
• The Journal of biological chemistry • 2013 • Systematic proteomic analysis identifies β-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic β-cell PMID:23430253

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