Nuovi meccanismi patogenetici da alterata adesione cellulare in patologie cardiovascolari e genodermatosi

Difficulties in studying genetic disorders come from phenomena of pleiotropism and genetic heterogeneity which often produce phenotypic overlapping. The advent of next generation sequencing (NGS) and a multidisciplinary approach, based on the interplay of clinic, genetic and functional biology studies, give us the possibility to deep investigate and amplify/rewrite many genetic conditions. An example of this synergic approach is illustrated in this work thesis whose findings are: i) the identification of genetics variants known to be associated with Multiple Self-Healing Squamous Epithelioma which we found to be involved also in the onset of Loeys-Dietz syndrome, ii) expansion of the phenotypic spectrum of Bartsocas-Papas and Curly hair-ankyloblepharon-nail dysplasia syndromes associated with mutations in Receptor Interacting Serine/Threonine Kinase 4 (RIPK4), and identification of nectin-4 as a new player of the p63 molecular network modulated by RIPK4, iii) the identification of phenotypic variability resulting from different mutations in Connexin 26 (GJB2) resulting in non-syndromic or syndromic hearing loss. In conclusion, the studies presented in this thesis highlight the paramount importance for a correct clinical and molecular diagnosis to plan a personalized medical approach based on individual genetic makeup.