Uncommon results of NF1 molecular analysis in a big family with numerous affected members

GILIBERTO F; FERRER M; LUCE L; SZIJAN I; PARMA D; FRANCIPANE L

Buenos Aires

Jornada; I Jornada de Divulgación de las Actividades del Departamento de Microbiología, Inmunología, Biotecnología y Genética de la Facultad de Farmacia y Bioquímica de la Universidad de Buenos Aires; 2018

Departamento de Microbiología, Inmunología, Biotecnología y Genética de la Facultad de Farmacia y Bioquímica de la Universidad de Buenos Aires

Neurofibromatosistype 1, the most common genetic disorder affecting the human nervous system, isthe result of loss-of-function mutations of the tumor suppressor NF1 geneand inherited in an autosomal dominant fashion. The condition predisposing individualsto the development of neurofibromas, optic nerve gliomas and skeletal abnormalities,is fully penetrant and has a highly variable expression, even within the samefamily. The molecular diagnosis of NF1 is still difficult due to the large sizeof the gene, the existence of pseudogenes, the lack of mutational hotspots andthe complex molecular spectrum. We studied familial NF1 in order to identifythe family members with the risk of developing the disease. The focus was themolecular testing of the two youngest members (4 years, 2 months) of a family thatincludes 11 affected individuals out of 19 total relatives. A simple and highly sensitivemethodology was used:  segregation analysis of four NF1 intragenicpolymorphic microsatellites (D17S1307, D17S1849, IVS27AC28.4, IVS38GT53.0) andmutational screening using bidirectional DNA sequencing of the NF1 exonsof interest. The analysis of the STRs revealed the at risk haplotype in the 7affected members studied and a different haplotype in 2 individuals who couldbe 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. Arecombination event was found between markers D17S1849 and IVS27AC28.4 in twoindividuals. Interestingly one of them was affected and the other wasasymptomatic. These data suggest that the mutation may be located between themarkers mentioned above. The data obtained are important for familial genetic counselling andallow the early diagnosis of predisposition to NF1. The finding of anintragenic recombination is an infrequent event in the NF1 syndrome.