We propose to utilize the power of whole exome sequencing (WES) to uncover new causes of Joubert syndrome (JS), a recessive neurodevelopment disorder affecting the cerebellum. Our currently funded NINDS award entitled """"""""Molecular characterization of Joubert syndrome"""""""" seeks to identify new causes through a variety of molecular strategies. Although our previous strategies involved whole genome SNP-scans, followed by candidate gene sequencing to arrive at identification of new JS causes, we have recently moved to WES as a highly efficient methodology that is optimized for recessive disease. Here we propose to study 20 inbred families with JS in which known causes have been excluded, that have not been previously undergone genome-wide SNP scans. We propose to send high-quality DNA samples on one proband from each family for this pilot study, with resultant high-quality WES reads to be returned to us shortly. These reads will then be subject to our established bioinformatics pipeline including HOMOZGYOSITY, SNP and INDEL callers in our lab to identify potentially deleterious sequence changes (PDSC). Next-phase analysis will include testing of each PDSC for segregation in the whole pedigree, for occurrence in a ethnically-matched cohort, as well as a defined cohort of JS patients, in order to validate new JS genes.
Pediatric recessive neurodevelopmental disorders are poorly understood, with almost no treatments available. This work will identify new genetic disease genes in the pathogenesis of Joubert syndrome, the most common inherited congenital ataxia disease, which can provide insights into developing new treatments. The preliminary written comments of the reviewers are reproduced below. These comments were prepared prior to the meeting and may not have been edited after the full committee discussion of your application.