Congenital ataxia presents in early childhood with non-progressive hypotonia, gross and fine motor delay and cognitive delays. These disorders are distinct from the progressive ataxias because of the presence of congenital cerebellar malformations and because they are typically inherited recessively. Joubert Syndrome and Related Disorders (JSRD) constitutes a subset of these conditions, consisting of a cerebellar midline (vermis) malformation, a nearly pathognomonic Molar Tooth sign on brain Imaging (MTI) and co-existent oculomotor apraxia and episodic breathing dysrhythmias. JSRD was thought to be monogenic until recently when clear evidence of both phenotypic and genotypic heterogeneity was demonstrated. Very little is known about the genetic causes of these midbrain/hindbrain malformations in humans, which has hindered proper diagnosis, prognosis, prenatal counseling and treatment. We have identified families mapping to 9q34.3 (MTI 1) with classical Joubert syndrome, and have genetically mapped a second locus associated with a form of JS displaying cerebellar, ocular and renal involvement (CORS) to chromosome 11 (MTI2). Furthermore, we have identified other families not linked to either locus, demonstrating further genetic heterogeneity. We plan to identify and characterize the genes and mutations responsible for JSRD. Families in whom the disorder is not linked to MTI1 or MTI2 will be studied using a general genetic linkage approach to identify additional MTI loci. We will perform mutation analysis on candidate genes linked to the MTI loci. A variety of positional cloning strategies will be utilized if candidate gene analysis is unsuccessful. Identification of JSRD genes coupled with extensive clinical data will allow us to characterize the spectrum of phenotypes caused by mutations in single genes and to compare phenotypes of patients with mutations at different loci. Of particular interest will be whether there is a correlation between specific genes and mutations with presence of autism, found to be present in a large proportion of JSRD patients. Molecular characterization of the JSRDs will lead to a new genetic classification and a better understanding of these disorders. Characterization of the pathogenic mechanisms underlying the JBRDs will lead to improved diagnosis, and will shed light on the genetics of human cerebellar development as well as more complex disorders including generalized ataxia and autism.
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