TCF25 – Cerebrovascular Disorder

TCF25, a gene located on an autosome, has emerged as a candidate locus associated with cerebrovascular disorder (MONDO_0011057). Two independent genome‑wide association studies have implicated TCF25 in modulating brain arterial diameters, an imaging endophenotype linked to cerebrovascular disease, in diverse populations (PMID:36778463, PMID:38038215). In the most robust analysis, 4150 participants from six population‐based cohorts were evaluated, and an intronic variant at TCF25 reached genome‑wide significance (rs35994878; P = 2.94×10^-8) for its association with the posterior brain arterial diameter (PMID:38038215).

Genetic evidence for this association is limited by the absence of familial segregation data or detailed variant-level pathogenicity analysis. While the significant GWAS signal provides statistical support, the variant is intronic and its functional consequence remains to be fully elucidated. No specific HGVS‐formatted coding change is reported, highlighting the need for future sequencing efforts to pinpoint causative alleles.

Complementary experimental evidence arises from functional studies using a Drosophila model. In these studies, the Drosophila ortholog of TCF25 (referred to as dNulp1) was shown to regulate Wingless (Wnt) signaling, a pathway critical for developmental processes. These assays, including rescue experiments and reporter assays, demonstrate that perturbation of dNulp1 leads to developmental abnormalities (PMID:29437009). However, the relevance of these findings to human cerebrovascular pathology remains indirect.

There are limitations to the current evidence. The genetic findings derive solely from GWAS data, which, while statistically significant, do not provide information on segregation in families or the direct impact of the variant on protein function in vascular tissues. Moreover, although the functional studies support a role in developmental signaling, they do not directly recapitulate the cerebrovascular phenotype observed in humans.

Integrating both lines of evidence, the association between TCF25 and cerebrovascular disorder is biologically plausible but remains preliminary. The statistical associations from multi‐ancestry cohorts and supportive experimental data, albeit indirect, together suggest that TCF25 may contribute to cerebrovascular regulation through effects on brain arterial structure. Additional studies, including deep sequencing and functional assays in relevant vascular models, are necessary to further clarify this relationship.

Key take‑home sentence: While current data provide limited genetic and moderate functional evidence linking TCF25 with cerebrovascular disorder, this association offers a promising target for further investigation to enhance diagnostic and therapeutic strategies.

References

• medRxiv • 2023 • Chromosome 10q24.32 Variants Associate with Brain Arterial Diameters in Diverse Populations: A Genome‑Wide Association Study PMID:36778463
• Journal of the American Heart Association • 2023 • Chromosome 10q24.32 Variants Associate With Brain Arterial Diameters in Diverse Populations: A Genome‑Wide Association Study PMID:38038215
• Current Molecular Medicine • 2018 • The bHLH Protein Nulp1 is Essential for Femur Development Via Acting as a Cofactor in Wnt Signaling in Drosophila PMID:29437009

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