Tissue-Specific Regulatory and Expression Patterns of CDG-causative genes account to Phenotypic Variability

Congenital disorders of glycosylation (CDGs) are rare metabolic diseases caused by impaired addition of glycans to proteins and lipids. They display wide clinical variability, but the molecular basis remains unclear. Using healthy transcriptomic data from the GTEx project (bulk: 2,833 samples across 36 tissues; single-nucleus: 209,126 nuclei from 25 samples spanning 8 tissue types and 44 cell types), we investigated the expression and regulatory landscapes of 12 CDG-causative genes.

CDG-causative genes were broadly but heterogeneously expressed, with both high and low expression aligning with clinical features. Interindividual variability in expression may contribute to phenotypic diversity in CDG. VPS13B was broadly expressed in fibroblasts, supporting their use in patient-derived models, while other genes showed more tissue-restricted expression, underscoring the importance of cellular context.

Several genes exhibited tissue-specific deviations from balanced biallelic expression. Five allelic expression types across individuals - biallelic balanced or biased, tissue-specific or constitutive monoallelic, and autosomal random monoallelic - suggest a role for allelic regulation in phenotypic heterogeneity.

Tissue-specific eQTLs highlighted regulatory complexity, with many variants located in intronic enhancers of unrelated genes.

Finally, gene expression-immune cell correlations recapitulated known immune phenotypes and suggested context-dependent immune roles.

Together, these findings reveal how genetic, regulatory, and immune factors shape CDG heterogeneity and provide a framework for future research.