Tailoring medical treatments for individual patients is at the core of personalized medicine. Clearly, to achieve that goal, one must address critical factors which dictate patient stratification, disease cause and symptoms. Even in the case of monogenic disorders which result from mutations within single and well-defined disease-causing genes, disease symptoms can vary dramatically. Whereas classical medical genetics has tended to distinguish between monogenic and multifactorial diseases, it is now increasingly evident that human diseases exist on a continuum between these two ends. Indeed, even siblings carrying the same mutation, occasionally display extremely divergent phenotypes, sometimes ranging between life-threatening phenotypes to absence of phenotype. This divergence is often thought to result from genetics modifiers (variations in DNA sequence that can modulate the phenotypic manifestations of a disease-causing mutations present in an independent target gene) and/or epigenetic (processes that alter gene function but  do not entail changes in the DNA sequence) mechanisms that control disease manifestations. Unfortunately, very little is currently known about the nature of these modifiers and this knowledge is instrumental for developing a personalized approach to disease medical management.
Here we propose to study this phenomenon in monogenic skin diseases were preliminary evidence pointing at the importance and possible contribution of genetic and epigenetic modifier mechanisms to phenotypic expression. In addition, epigenetic mechanisms are known to play critical roles in skin homeostasis, wound repair and pathology.
We plan to perform deep phenotypic and functional characterization in two representative and paradigmatic groups of monogenic skin diseases: epidermolysis bullosa (EB) resulting from defective function of the dermo-epidermal junction and disorders of cornification (DOC) which are associated with defective formation and/or function of the epidermal barrier.
We will study those model monogenic diseases using the following approach: We will (i) define the causal events in unresolved EB or DOC cases wherein mutation analysis has not yet revealed a causal mutation, (ii) delineate potential genetic and epigenetic modifiers of phenotypic expressivity in these two conditions, and finally, (iii) study the contribution of identified modifiers to phenotype expressivity using animal and patients specific cellular models.
Should this project be successful, it is likely to significantly broaden our understanding of disease pathogenesis and clinical manifestations as well as lead to improved innovative approaches to diagnosis and treatment of skin and other diseases.