IDENTIFICATION OF DE-NOVO DELETIONS AT THE NF1 GENE - NO PREFERENTIALPATERNAL ORIGIN AND PHENOTYPIC ANALYSIS OF PATIENTS

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder . To date, a relatively small number of NF1 mutations have been charac terized, thus precluding genotype-phenotype correlations. By genotypin g 75 NF1 families, we have detected six hemizygous patients (two of wh om are members of the same family). The five presumed deletions were c onfirmed by two quantitative methods of analysis of NF1 copy number: S outhern hybridization with cDNA probes and a single-strand conformatio n polymorphism analysis that discriminates between the NF1 gene and th e pseudogene sequences. The five deletions remove most of the NF1 gene , at least 225 kb, from exon 9 to the 3' end of the coding sequence. T he origin of de novo mutations in the NF1 gene has been reported to be mainly paternal but we have determined that four of the de novo delet ions involved the maternal chromosome and one the paternal chromosome. The six patients with deletions exhibited precocious, multiple clinic al features of the disease. The incidence of tumor complications, part icularly plexiform neurofibromas and intracranial tumors, among this g roup of patients is higher than the observed incidence in our NF1 popu lation, suggesting that NF1 haploinsufficiency may cause a more severe phenotype with regard to tumor development. In contrast to other repo rts that associated large deletions with mildly dysmorphic facies, men tal retardation and a large number of cutaneous neurofibromas, only on e out of our six patients presented this phenotype.