OBJECTIVETo report a heterozygous RNA-splicing mutation (IVS3+ 3A to C) of NF2 gene in a Chinese family with autosomal dominant neurofibromatosis type II and investigate the relationship between the genotype and phenotype.

METHODSThe proband with bilateral vestibular schwannomas underwent gamma knife radiosurgery two years earlier. DNA of blood samples from all affected individuals, suspected individuals and unaffected relatives of the family was extracted and amplified to detect the polymorphisms at loci D22S1150 and D22S268 that are linked with the NF2 gene. Two-point LOD score was calculated. The promoter region, 17 exons and exon/intron boundaries of NF2 gene were amplified and sequenced for the proband. The exon 3/intron 3 boundaries of NF2 gene was amplified and sequenced for the other 3 patients, 1 suspected individual, 9 unaffected members of the family and 150 unrelated controls.

RESULTSThe result of two-point linkage analysis suggested that NF2 gene was a candidate gene (Zmax= 2.109, θ = 0.00, locus D22S1150). DNA sequencing revealed a heterozygous splicing mutation in intron 3 (IVS3+ 3A to C) for the proband. Identical mutation was also observed in the other 3 patients and 1 suspected individual. No mutation was found in the 9 normal family members and 150 unrelated controls, which was consistent with the clinical diagnosis.

CONCLUSIONThis is the first report of familial neurofibromatosis type II with a splicing mutation of IVS3+ 3A to C of the NF2 gene. The mutation might be responsible for the neurofibromatosis type II in the family.