MISLEADING LINKAGE RESULTS IN AN NF2 PRESYMPTOMATIC TEST OWING TO MOSAICISM

A two generation family with neurofibromatosis type 2 (NF2) is present ed in which a family member requested presymptomatic molecular diagnos is. Since the consultand's mother had clinically well defined NF2, he was quoted to be at 50% risk of carrying an NF2 mutation. Mutation scr eening in the mother did not show the causative mutation and, conseque ntly, presymptomatic testing was based on linkage analysis. This showe d that the consultand carried the high risk chromosome 22. Subsequent mutation screening of his clinically affected sister showed a nonsense mutation, R262X in exon 8 of the NF2 gene. The mother turned out to b e a mosaic for R262X; the son had not inherited the mutation. Mosaicis m may be a common mechanism in NF2 and other autosomal dominant diseas es with a high new mutation rate. This may be one explanation for a di fference in expression in generations. Caution has to be exercised whe n giving results based on Linkage tests which imply a very high risk t o people in the second generation.