Analysis of CpG C-to-T mutations in neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a dominant disorder caused by mutations in the NF1 gene; approximately 100 NF1 gene mutations have been published. The CpG C‐to‐T transition is a frequent mutation mechanism in genetic disorders. To estimate its frequency in NF1, we employed a PCR‐restriction digestion method to examine 17 CpGs in 65 patients, and also screened for a CpG nonsense transition (R1947X) that occurs in 1‐2% of patients. The analysis revealed disease‐related CpG C‐to‐T transitions (including a nonsense mutation that may be as frequent as R1947X) as well as a benign variant and another mutation at a CpG. Four patients showed CpG mutations in analysis of 18 sites (17 surveyed by restriction digest, plus the R1947X assay), including three C‐to‐T transitions and one C‐to‐G transversion. These 18 sites represent one‐fifth of the 91 CpGs at which a C‐to‐T transition would result in a nonsense or nonconservative missense mutation. Thus, it is feasible that the CpG mutation rate at NF1 might be similar to that seen in other disorders with a high mutation rate, and that recurrent NF1 mutations may frequently reside at CpG sites. Hum Mutat 11:411, 1998. © 1998 Wiley‐Liss, Inc.