Neurofibromatosis Type 1 Due to Germ-Line Mosaicism in a Clinically Normal Father

Abstract

Background: The mutation rate of the neurofibromatosis type 1 (NF1) gene 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 neurofibromatosis type 1 occurred in two siblings with clinically normal parents, and we demonstrate germ-line mosaicism in the father. Methods: We studied lymphocyte DNA from each member of the family and the father's spermatozoa for several polymorphic intragenic markers of the NF1 gene. Southern blots of DNA digested with several enzymes were hybridized with complementary DNA and individual NF1 exon probes to search for alterations in the gene. Results: The affected siblings, with a clinically 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. Analysis with probes from this region of the NF1 gene showed a 12-kb deletion of the NF1 gene, involving exons 32 to 39, in the affected offspring. Ten percent of the father's spermatozoa carried the same NF1 deletion, but the abnormality was not detected in DNA from his lymphocytes. Conclusions: The presence of the NF1 mutation in 10 percent of the clinically normal father's spermatozoa supports the hypothesis that most germ-line mutations occur in precursors of gametes. In cases of spontaneous mutation, analyzing the specific NF1 mutation in the father's sperm might help in the detection of mosaicism and thus facilitate genetic counseling about further pregnancies., Neurofibromatosis type 1, or von Recklinghausen's disease, is one of the most common autosomal dominant disorders, with an incidence of approximately 1 in 3500. The main clinical features of the disease are cafe au lait spots, cutaneous neurofibromas, and hamartomas of the iris (Lisch nodules). Several complications can occur, including central nervous system tumors, scoliosis, plexiform neurofibromas, learning difficulties, and epilepsy1,2. The gene for neurofibromatosis type 1 (the NF1 gene), located on chromosome 17, has been isolated3–5 and found to encode an amino acid sequence (neurofibromin) homologous to the catalytic region of mammalian ras guanosine triphosphatase6,… © 1994, Massachusetts Medical Society. All rights reserved.