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Neurofibromatosis type I is an autosomal dominant disease with complete penetrance and variable age-dependent expressivity. It is caused by heterozygous mutations in neurofibromin 1 (NF1). These occur throughout the length of the gene, with no apparent hotspots. Even though some mutations have been found repeatedly, most have been observed only once. This, along with the variable expressivity, has made it difficult to establish genotype-phenotype correlations. Here, we report the clinical and molecular characteristics of four pediatric patients with neurofibromatosis type I. Patients were clinically examined and DNA was extracted from peripheral blood. The whole coding sequence of NF1, plus flanking intronic regions, was examined by Sanger sequencing, and four frameshift mutations were identified. The mutation c.3810_3820delCATGCAGACTC was observed in a familial case. This mutation occurred within a sequence comprising two 8-bp direct repeats (GCAGACTC) separated by a CAT trinucleotide, with the deletion leading to the loss of the trinucleotide and the 8-bp repeat following it. The deletion might have occurred due to misalignment of the direct repeats during cell division. In the mutation c.5194delG, the deleted G is nested between two separate mononucleotide tracts (AAAGTTT), which could have played a role in creating the deletion. The other two mutations reported here are c.4076_4077insG, and c.3193_3194insA. All four mutations create premature stop codons. In three mutations, the consequence is predicted to be loss of the GAP-related, Sec14 homology, and pleckstrin homology-like domains; while in the fourth, only the latter two domains would be lost.

Dr. García Hernández N.

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