Characterization of NF1 frameshift mutations in pediatric patients with neurofibromatosis type I.

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.

A familial reciprocal translocation t(1;15) in three generations identified in a regular trisomy 21 patient.

The concurrence of a reciprocal translocation and an aneuploidy represent a rare coincidence and an interchromosome effect between these two events has been suggested. We report the case of a family with a t(1;15) in three generations which was identified through the evaluation ofa patient with classical trisomy 21 or Down syndrome. The cytogenetic analysis with GTG banding showed that the proband had a regular trisomy 21 and a balanced translocation t(1;15). FISH and microsatellite analysis were carried out in the family in order to discard an interchromosomal effect. The implications for genetic assessment are discussed.