Title:  Energy and pathogenicity: Case study of X-linked monogenic diseases
Abstract:  Folding and binding free energies are essential for assessing stability and binding affinity of biological macromolecules. Changes of these quantities caused by missense mutations may or may not be associated with pathogenicity. We argue that for monogenic diseases, the most prominent pathogenic effect is associated with changes of these two quantities. This allows us to use computational approaches to predict the effect of missense mutations on thermodynamics and to infer pathogenicity. Such an approach offers two advantages over the classical pathogenicity predictors: it can do confident predictions even for low conserved sequences and paves the way for development of treatment via development of stabilizers or modulators. We apply it to study several X-linked disorders (Snyder-Robinson, Rett and Creatine Deficiency syndromes) and demonstrate that many genotypes result in the same phenotype, which allows the same treatment to be applied to different genotypes. Furthermore, it can be used for genetic screening of prospective mothers or in-vitro fertilization, since these variants typically do not occur de-novo but are inherited from the carrier mother.