CLINICAL AND MOLECULAR CHARACTERIZATION OF JOUBERT SYNDROME AND RELATED DISORDERS

Joubert Syndrome is an autosomal recessive syndrome presenting with hypotonia, ataxia, psychomotor delay, oculomotor apraxia and behavioral problems. Neuroradiologically, JS is characterized by a peculiar brainstem malformation, the “Molar Tooth Sign” (MTS). The key JS features can be associated with defects in other organs (mainly retina and kidneys), identifying a large spectrum of disorders of variable severity sharing the MTS, named “Joubert syndrome related disorders (JSRD)”. Two loci and five genes have been identified, all encoding for ciliary proteins. Mutations in these genes account for only 25-30% of JSRD cases, but are also causative of overlapping conditions such as isolated nephronophthisis and Meckel syndrome. The extreme clinical and genetic heterogeneity of JSRDs has so far hindered proper diagnosis, prognosis, genetic counseling and management of patients. Since 2002, both PIs have been actively researching JSRD, with the following results: 1) recruitment and clinical characterization of a large cohort of JSRD patients; 2) identification of the CEP290 gene; 3) mapping of the JBTS2 locus; 4) mutation screening of AHI1, NPHP1 and CEP290 genes; 5) gene-phenotype correlates; 6) proposal of a new clinical-genetic classification. Objective of this project is to increase the current knowledge of JSRDs. This will be accomplished by molecular analysis of known genes in about 400 patients representative of the full JSRD spectrum; gene-phenotype correlates; evaluation of oligogenic inheritance in JSRD; identification of one or more novel genes. The outcome of this study will help develop efficient strategies for pre- and post-natal molecular diagnosis, identify accurate prognostic indexes and specific diagnostic and follow-up algorithms for patients. In turn, these will improve genetic counseling and help treat or delay the progression of associated conditions such as renal failure and behavioral problems.