Genotype Phenotype Relationship in Neurofibromatosis 2

Massachusetts General Hospital, Boston MA

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Abstract

DESCRIPTION (provided by the applicant): Neurofibromatosis 2 (NF2) is a genetic disorder characterized by the development of multiple nervous system tumors. Although there is great heterogeneity in the NF2 population as a whole, remarkable homogeneity is seen within families. The hypothesis of our proposal is that there is a correlation between the highly variable phenotype of neurofibromatosis 2 and the causative genotype. We will explore this hypothesis with three specific aims. 1) To define a cohort of uniformly studied NF2 patients, create a database of their clinical characteristics, and a repository of tissue samples required for aims 2 and 3. 2) To determine the effect of type and location of mutation on phenotype in the 66% of NF2 patients who harbor point mutations, and small frameshifts of the NF2 gene and the mechanism of mutation in the 33% of predominantly mildly affected patients, whose mutations cannot be determined by exon scanning. 3) To explore the feasibility of a rapid molecular diagnostic test for NF2-based on the findings of aims 1 and 2. Should our hypothesis be correct, these studies may be expected to shed light on the molecular basis for tumor suppression in NF2 by identification of critical regions of the transcript and alternative mechanisms of inactivation of this protein. They will also clarify the role of molecular analysis in the initial ascertainment of persons with NF2 and related phenotypes. Finally, the determination of genotype-phenotype relationships will aid in the prognostication and effective management of this devastating disorder.