Joubert syndrome: beyond conventional mendelian genetics

Research on rare genetic disorders has long focused on the identification of causative genes. Yet, despite the huge progresses brought by next-generation-sequencing, many patients still remain without a genetic diagnosis, and identified mutations are often not easily interpreted. An example is Joubert syndrome (JS), a recessively inherited rare disorder associated to over 40 genes and characterized by a wide clinical spectrum, in which a genetic diagnosis is reached only in 60-70% cases. The project proposes to validate three hypotheses in JS, based on a large cohort of patients and consolidated preliminary data: 1) A subset of undiagnosed JS cases may be caused by “cryptic” mutations which cannot be identified by conventional techniques (e.g. mutations in non-coding DNA or structural genomic alterations). Such mutations will be searched through bioinformatic analysis of genomic data and then validated in lab. 2) Distinct mutations may have variable effects on the protein’s function, directly impacting on clinical manifestations. The pathogenic effect of different missense variants will be evaluated using bioinformatic modelling and in vitro models. 3) The variable multiorgan involvement of patients mutated in the same gene may depend on tissue-specific modulation of the expression of the mutant gene and related pathways. Patient-derived induced pluripotent stem cells will be differentiated in distinct lineages and assessed for their cellular phenotypes and gene expression profiles. The outcome of this project is expected to improve diagnosis and prognostic indications of patients with JS, representing a model also for other rare monogenic diseases.