Molecular characterization of germline NF2 gene rearrangements

Neurofibromatosis type 2 (NF2) is an autosomal dominant disease that causes a predisposition to nervous system tumors, Deleterious point mutations hav e been found in about 55% of NF2 patients, and large genomic deletions acco unt for approximately 33% of NF2 gene alterations. The majority of these de letions are larger than 50 kb, with a breakpoint usually lying outside the NF2 gene. We identified two cases of intragenic deletion with loss of 1.5 a nd 40 kb, respectively. In both cases, one boundary of the deletion was loc ated in or at the proximity of an SVA sequence in NF2 intron 4. No sequence identity longer than 5 bases and no signal of specific recombination have been evidenced on either side of the deletion breakpoints. These observatio ns are compatible with a nonhomologous recombination being responsible for the genomic deletions. In a third case, a paracentric inversion of chromoso me 22 was found. This chromosomal rearrangement breaks the NF2 gene in two parts and carries the first NF2 exon in a juxta-centromeric position. The v ariability in position of the deletions and the observation of a new chromo somal rearrangement in the NF2 gene underscore the importance of FISH analy sis in the molecular diagnosis of NF2. (C) 2000 Academic Press.