GERM-LINE MUTATIONS IN THE NEUROFIBROMATOSIS-2 GENE - CORRELATIONS WITH DISEASE SEVERITY AND RETINAL ABNORMALITIES

Neurofibromatosis 2 (NF2) features bilateral vestibular schwannomas, o ther benign neural tumors, and cataracts. Patients in some families de velop many tumors at an early age and have rapid clinical progression, whereas in other families, patients may not have symptoms until much later and vestibular schwannomas may be the only tumors. The NF2 gene has been cloned from chromosome 22q; most identified germ-line mutatio ns result in a truncated protein and severe NF2. To look for additiona l mutations and clinical correlations, we used SSCP analysis to screen DNA from 32 unrelated patients. We identified 20 different mutations in 21 patients (66%): 10 nonsense mutations, 2 frameshifts, 7 splice s ite mutations, and 1 large in-frame deletion. Clinical information on 47 patients from the 21 families included ages at onset and at diagnos is, numbers of meningiomas, spinal and skin tumors, and presence of ca taracts and retinal abnormalities. We compared clinical findings in pa tients with nonsense or frameshift mutations to those with splice-site mutations. When each patient was considered as an independent random event, the two groups differed (P less than or equal to .05) for nearl y every variable. Patients with nonsense or frameshift mutations were) lounger at onset and at diagnosis and had a higher frequency and mean number of tumors, supporting the correlation between nonsense and fram eshift mutations and severe NF2. When each family was considered as an independent random event, statistically significant differences betwe en the two groups were observed only for mean ages at onset and at dia gnosis. A larger data set is needed to resolve these discrepancies. We observed retinal hamartomas and/or epiretinal membranes in nine patie nts from five families with four different nonsense mutations. This fi nding, which may represent a new genotype-phenotype correlation, merit s further study.