Interpretation of Test Results

The detection of a truncated neurofibromin polypeptide by PTT can result in false positives.21 High specificity requires identifying the underlying mutation at the genomic DNA or cDNA level, or both, since false positives can arise during sample handling (see Laboratory Issues below). The interpretation of missense and subtle in-frame alterations as pathogenic mutations rather than neutral polymorphisms is complicated by the lack of a functional assay for neurofibromin. Apparent recurrence of a putative mutation requires careful study of the literature, since not all NF1 mutation studies sequenced the entire gene. No comprehensive NF1 mutation database is available; however, some mutations have been submitted to the Human Gene Mutation Database (http://archive.uwcm.ac.uk/uwcm/mg/ hgmd0.html), and the largest NF1 database is actively managed and analyzed by Jan Friedman (http://www. medgen.ubc.ca/friedmanlab/).

Although most likely rare, affected family members with different independent NF1 inactivating mutations have been reported,27 presumably a reflection of the high mutation rate of the gene (~105/gamete/generation). The interpretation of FISH with NF1 probes can be complicated by mosaicism for an NF1 microdeletion; therefore, an appropriate number of cells must be analyzed.16 The frequency of mosaicism for an NF1 mutation is not known; however, this is likely the underlying mechanism for patients with segmental or localized signs of the disorder.

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