CONICET | Buscador de Institutos y Recursos Humanos

Neurofibromatosis type 1, the most common genetic disorder affecting the human nervous system, is the result of loss-of-function mutations of the tumor suppressor NF1 gene and inherited in an autosomal dominant fashion. The condition predisposing individuals to the development of neurofibromas, optic nerve gliomas and skeletal abnormalities, is fully penetrant and has a highly variable expression, even within the same family.The molecular diagnosis of NF1 is still difficult due to the large size of the gene, the existence of pseudogenes, the lack of mutational hotspots and the complex molecular spectrum. We studied familial NF1 in order to identify the family members with the risk of developing the disease. The focus was the molecular testing of the two youngest members (4 years, 2 months) of a family that includes 11 affected individuals out of 19 total relatives.A simple and highly sensitive methodology was used: segregation analysis of four NF1 intragenic polymorphic microsatellites (D17S1307, D17S1849, IVS27AC28.4, IVS38GT53.0) and mutational screening using bidirectional DNA sequencing of the NF1 exons of interest. The analysis of the STRs revealed the at risk haplotype in the 7 affected members studied and a different haplotype in 2 individuals who could be excluded from the risk. The analysis of the two probands (still unaffected children) indicated that one of them carries the at risk haplotype while the other carries the different one.A recombination event was found between markers D17S1849 and IVS27AC28.4 in two individuals. Interestingly one of them was affected and the other was asymptomatic. These data suggest that the mutation may be located between the markers mentioned above.The data obtained are important for familial genetic counselling and allow the early diagnosis of predisposition to NF1. The finding of an intragenic recombination is an infrequent event in the NF1 syndrome.