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Two independent multi‑patient studies have implicated SYNDIG1L (HGNC:32388) in Alzheimer disease (MONDO_0004975) through analyses of CpG‐related single nucleotide polymorphisms (CGS) that serve as a nexus for both genetic and epigenetic influences. In one study of 7,155 Caribbean Hispanic participants and 1,283 Non‑Hispanic Whites (PMID:39177846), an intergenic locus between VRTN and SYNDIG1L yielded a significant association (Score = –37.67, P < 1e–9) indicating a robust genetic signal. A second study in a similar multi‑ethnic cohort confirmed the association with a combined dosage analysis, reporting a CGS dosage effect between VRTN (Score = –19.6, P < 1e–8) and SYNDIG1L (Score = –37.7, P < 1e–9) (PMID:38405911).
While the genetic association is statistically compelling across large sample sizes, functional follow‑up experiments provided only limited supportive evidence. Specifically, in brain tissue analyses the methylation levels at the SYNDIG1L locus did not significantly modulate downstream mRNA expression (P = 0.08) (PMID:39177846), tempering the overall functional evidence for pathogenicity. No coding variants meeting the prescribed HGVS criteria were explicitly reported for SYNDIG1L in these studies.
Both studies used a robust genome‑wide sliding‑window approach to delineate the genetic landscape of Alzheimer disease risk, yet the absence of segregation data and a clear downstream functional consequence for SYNDIG1L necessitates cautious interpretation. The aggregate evidence supports a moderate gene‑disease association, with strong genetic signals counterbalanced by limited experimental confirmation.
In summary, while SYNDIG1L is significantly associated with Alzheimer disease through large‑scale CGS dosage analysis, further functional studies are needed to establish its mechanistic role. This integrated assessment provides a useful framework for diagnostic decision‑making and commercial application in risk stratification and therapeutic targeting.
Gene–Disease AssociationModerateLarge multi‑ethnic cohorts demonstrated genome‑wide significant association between CGS dosage at the SYNDIG1L locus and Alzheimer disease (PMID:39177846; PMID:38405911), tempered by limited evidence for downstream functional impact. Genetic EvidenceStrongRobust CGS dosage effects were observed in >8,400 participants with highly significant p‑values (e.g., Score = –37.7, P < 1e–9) indicating a strong genetic association. Functional EvidenceLimitedBrain methylation analysis failed to show significant modulation of mRNA expression at the SYNDIG1L locus (P = 0.08), thus providing only limited experimental support. |