Clinical and molecular insights into Wiedemann-Rautenstrauch syndrome: A case report and genetic analysis of the c.2707G>A variant in the POLR3A gene

Abstract

Wiedemann-Rautenstrauch syndrome (WRS) is a rare neonatal progeroid disorder primarily associated with pathogenic variants in POLR3A. However, the pathogenicity of certain variants remains unclear. Here, we report a WRS case carrying the POLR3A c.2707G > A (p.Gly903Arg) variant and explore its potential role in disease pathogenesis through in silico predictive and structural modeling analyses. Evolutionary conservation analysis, along with functional impact predictions from Provean, SIFT, PolyPhen−2, MutationTaster, MutPred2, Align GVGD, SNAP, and PhD-SNP, consistently classified the variant as deleterious. Splicing predictions using Human Splicing Finder (HSF) and SpliceAI suggested disruption of regulatory motifs and activation of a cryptic splice site. To find potential structural consequences, molecular modeling of the wild-type and mutant RNA polymerase III complex (PDB: 7DN3) was performed using PyMOL, while DynaMut analysis revealed destabilizing effects, decreased residue flexibility, and steric clashes that could impair complex function. By integrating genetic, computational, and structural approaches, this study not only provides a comprehensive characterization of the POLR3A c.2707G > A (p.Gly903Arg) variant but also contributes to the expanding spectrum of genetic findings in WRS. Our findings highlight the importance of case reports in refining genotype-phenotype correlations and emphasize the need for further functional validation to elucidate the molecular mechanisms underlying WRS.