The prevalence of protein misfolding as a mechanism for hereditary deafness.

Incorporating protein misfolding stability into Bayesian models identifies over 28,000 likely pathogenic deafness variants, revealing a key disease mechanism.

• Why it matters: Understanding the role of protein misfolding in hereditary deafness addresses a critical gap in classifying uncertain genetic variants, improving diagnosis and treatment options.
• What they did: The study evaluated 381,924 missense variants across 224 genes using probabilistic frameworks, integrating computational predictions and biophysical data, especially protein folding stability.
• The result: Over 28,000 variants were prioritized as likely pathogenic based on protein destabilization, enabling genetic diagnosis upgrades in twelve cases and highlighting structural disruption as a disease mechanism.