TYPE OF MUTATION IN THE NEUROFIBROMATOSIS TYPE-2 GENE (NF2) FREQUENTLY DETERMINES SEVERITY OF DISEASE

The gene predisposing to neurofibromatosis type 2 (NF2) on human chrom osome 22 has revealed a wide variety of different mutations in NF2 ind ividuals. These patients display a marked variability in clinical pres entation, ranging from very severe disease with numerous tumors at a y oung age to a relatively mild condition much later in life. To investi gate whether this phenotypic heterogeneity is determined by the type o f mutation in NF2, we have collected clinical information on 111 NF2 c ases from 73 different families on whom we have performed mutation scr eening in this gene. Sixty-seven individuals (56.2%) from 41 of these kindreds revealed 36 different putative disease-causing mutations. The se include 26 proposed protein-truncating alterations (frameshift dele tions/insertions and nonsense mutations), 6 splice-site mutations, 2 m issense mutations, 1 base substitution in the 3' UTR of the NF2 cDNA, and a single 3-bp in-frame insertion. Seventeen of these mutations are novel, whereas the remaining 19 have been described previously in oth er NF2 individuals or sporadic tumors. When individuals harboring prot ein-truncating mutations are compared with cases with single codon alt erations, a significant correlation (P < .001) with clinical outcome i s observed. Twenty-four of 28 patients with mutations that cause prema ture truncation of the NF2 protein, schwannomin, present with severe p henotypes. In contrast, all 16 cases from three families with mutation s that affect only a single amino acid have mild NF2. These data provi de conclusive evidence that a phenotype/genotype correlation exists fo r certain NF2 mutations.