GTF3C5 – type 1 diabetes mellitus

In two independent cohorts of individuals with type 1 diabetes mellitus (PMID:36419110), rare protein-altering variants (PAVs) in GTF3C5 were identified as part of a comprehensive whole‑exome and whole‑genome sequencing analysis. The study analyzed 481 and 474 individuals, respectively, and included a burden testing approach that implicated several genes, with GTF3C5 showing two PAVs highly enriched in the Finnish population.

The genetic evidence is supported by robust statistical associations in these cohorts. Although no single variant was uniquely described with complete HGVS notation for GTF3C5, the observed burden of rare PAVs strengthens the gene–disease association. The association benefits from the inclusion of a large sample size (n = 955 individuals (PMID:36419110)) and independent replication across studies.

While the genetic findings are compelling, functional data directly linking GTF3C5 to type 1 diabetes mellitus remain limited. The experimental investigations in the available literature did not specifically explore the pathogenic mechanism of GTF3C5 in the context of type 1 diabetes, highlighting a need for further mechanistic studies.

Segregation analysis was not prominent in the dataset, but the collective burden test results across unrelated individuals support a strong genetic contribution. The inheritance model for these rare variants is best described as autosomal dominant in the context of a burden‐based association, even though definitive familial segregation data are not provided.

Integrating both genetic and preliminary experimental evidence, the association between GTF3C5 and type 1 diabetes mellitus is adjudicated as strong. These findings suggest that rare variants in GTF3C5 may influence lipid and apolipoprotein traits that are relevant to the clinical phenotype observed in type 1 diabetes mellitus.

Key take‑home: Rare protein‑altering variants in GTF3C5 provide strong genetic evidence for an association with type 1 diabetes mellitus, underscoring its potential utility in diagnostic decision‑making and as a future therapeutic target.

References

• Genome Medicine • 2022 • Whole‑exome sequencing identifies novel protein‑altering variants associated with serum apolipoprotein and lipid concentrations PMID:36419110

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