NEUROFIBROMATOSIS TYPE-1 DUE TO GERM-LINE MOSAICISM IN A CLINICALLY NORMAL FATHER

Background. The mutation rate of the neurofibromatosis type 1 (NF1) ge ne is one of the highest in the human genome, with about 50 percent of cases being due to new mutations. We describe a family in which neuro fibromatosis type 1 occurred in two siblings with clinically normal pa rents, and we demonstrate germ-line mosaicism in the father. Methods. We studied lymphocyte DNA from each member of the family and the fathe r's spermatozoa for several polymorphic intragenic markers of the NF1 gene. Southern blots of DNA digested with several enzymes were hybridi zed with complementary DNA and individual NF1 exon probes to search fo r alterations in the gene. Results. The affected siblings, with a clin ically severe form of neurofibromatosis type 1, showed no inheritance of paternal alleles for a marker in intron 38 of the NF1 gene, whereas they received alleles from both parents for other NF1 markers. Analys is with probes from this region of the NF1 gene showed a 12-kb deletio n of the NF1 gene, involving exons 32 to 39, in the affected offspring . Ten percent of the father's spermatozoa carried the same NF1 deletio n, but the abnormality was not detected in DNA from his lymphocytes. C onclusions. The presence of the NF1 mutation in 10 percent of the clin ically normal father's spermatozoa supports the hypothesis that most g erm-line mutations occur in precursors of gametes. In cases of spontan eous mutation, analyzing the specific NF1 mutation in the father's spe rm might help in the detection of mosaicism and thus facilitate geneti c counseling about further pregnancies.