Abnormalities of the human hindbrain are present in Joubert syndrome and closely related cerebello-ocular-renal syndromes, and other often poorly classified cerebellar malformation disorders. Although these disorders are clinically diverse and genetically heterogeneous, they are now more accurately and reliably identified by cranial MRI scanning. However, the genetic, biochemical, and pathophysiological bases of such malformations remains largely unknown. The purpose of this project is to identify genes responsible for Joubert syndrome, Joubert syndrome-related disorders, and other cerebellar-hindbrain malformations in order to gain insights into the normal development and function of the cerebellum. In this application, the candidate will undertake patient-oriented research and mentor trainee/junior faculty members to facilitate research into the basis of human cerebellar malformations. The specific objectives are to clarify the clinical features and spectrum of this complex group of disorders by improved ascertainment with refined clinical studies to enhance diagnostic accuracy as a prelude to gene identification. The candidate intends to gain insight into the molecular basis of these hindbrain malformations by evaluating candidate genes suggested from: (i) a causative role for an overlapping or allelic disorder; (ii) disease associated chromosomal rearrangements; (iii) integrated phenotyping and genetic mapping in cerebellar developmental disorders utilizing consanguineous pedigrees. By these means, the candidate intends to derive logical correlations between the underlying molecular pathology and the features of these disorders. Identification of causal genes for such malformations would provide insights into aberrant cerebellar developmental processes, which result in hindbrain malformations. In addition, the identification of such genes in conjunction with improved clinical nosology would enhance the accuracy of biomedical diagnosis, provide precise recurrence risks to families, and potentially generate options for early prenatal diagnosis. Furthermore, accurate diagnosis by these methods would provide the basis for longitudinal clinical studies, improve the quality of information, health care and management recommendations for such individuals and their families and ultimately, improve the prospect for specific therapies.
