PHENOTYPIC VARIABILITY ASSOCIATED WITH 14 SPLICE-SITE MUTATIONS IN THE NF2 GENE

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder cause d by mutations in the NF2 gene. Patients carrying NF2 mutations are pr edisposed to cerebral and spinal tumors with bilateral vestibular schw annomas as the hallmark. Using single strand conformation polymorphism and temperature gradient gel electrophoresis analysis, we have screen ed 87 unrelated NF2 patients for mutations in the NF2 gene. In this st udy, we report phenotypes associated with 14 splice-site mutations car ried by 14 propositi and 11 relatives. The mutations were distributed in exons 2, 3, 5, 7, 8, 14, and 15. These splice-site mutations were a ssociated with various phenotypes, from severe to asymptomatic. Phenot ypic variation was also observed within families. Mutations downstream from exon 8 resulted more often in mild phenotypes. No meningiomas we re found in any of 13 affected or mutation bearing individuals from th ree families with splice-site mutations of exons 14 and 15, These data suggest that splice-site alteration is a relatively common cause of N F2, and that unlike other mutations the clinical outcomes of splice-si te mutations in the NF2 gene are variable. These results add to the gr owing body of information on genotype-phenotype correlation in NF2. (C ) 1998 Wiley-Liss, Inc.