Frontiers in genetics
Molecular characterization and pathogenicity stratification of YWHAG missense variants in developmental and epileptic encephalopathy
By Liu WH, Zhou J, Zhu ZY and 4 others.
Abstract
Background
Variants in YWHAG cause severe developmental and epileptic encephalopathy (DEE) with early-onset seizures. Rapid and precise clinical classification of its missense variants presents a substantial challenge. This study sought to explore YWHAG spatiotemporal expression-pathogenicity correlation and reliable pathogenicity indicators for its variants to promote clinical genetic diagnosis.
Methods
In this study, 55 YWHAG missense variants were curated, including 17 pathogenic/likely pathogenic variants that met ACMG guideline criteria and 38 benign variants from gnomAD. We performed protein structure modeling, spatiotemporal expression profiling, single-cell transcriptome analysis, PPI network construction, and functional enrichment analysis. We also evaluated 34 pathogenicity prediction tools using accuracy, balanced accuracy, AUC, and MCC.