Clinical, genetic and functional studies on Joubert syndrome and related disorders: a model to understand the complexity of ciliopathies

Joubert syndrome and related disorders (JSRD) are autosomal recessive or X-linked ciliopathies presenting with hypotonia, ataxia, psychomotor delay, multiorgan involvement, and a peculiar mid-hindbrain malformation (the Molar Tooth Sign). So far, 21 causative genes have been identified, but their overall mutational load and phenotype correlates remain unknown. All genes encode ciliary proteins, and there is marked clinical-genetic overlap with other ciliopathies. The great phenotypic variability associated with mutations in the same gene suggests the existence of genetic modifiers and oligogenic inheritance. Objectives of this project are to increase knowledge on the clinical, genetic and functional basis of Joubert syndrome and related disorders. Out of 420 families with Joubert syndrome and related disorders recruited, DNA samples from about 300 are adequate for next generation sequencing studies, including 68 patients carrying mutations in known genes. This cohort will undergo NGS-based target resequencing of 79 genes causative of human ciliopathies. Multiplex and/or consanguineous families in which no mutations are found will undergo whole exome sequencing to identify novel causative genes. We will also characterize in detail the cerebellar development of JSRD mouse models, with respect to neurogenesis, ciliary development, and functional interactions with signaling pathways of relevance in cerebellar development and ciliopathies alike. The project is expected to largely increase our knowledge of J Joubert syndrome and related disorders, and will improve diagnostic tools, management and treatment of these and potentially other ciliopathies.