Genotype-phenotype correlation in patients with NF1 microdeletion syndrome : identification of candidate genes for mental retardation

NF1 microdeletion syndrome is determined by haploinsufficiency of NF1 gene and its flanking regions in 17q11.2. As indicated in previous studies microdeleted patients (pts) show a more severe phenotype than that observed in classical NF1 pts. To address a phenotype-genotype correlation we have undertaken a study aimed at: 1) grouping the pts on the basis of their extra-NF1 clinical signs; 2) searching candidate genes involved in the outcome of severe phenotype. As NF1 microdeleted pts account for 5-8% of NF1 mutations, we combined the clinical and genetic evidence from 15 of our pts with that concerning 77 similar published cases to evaluate the frequency of each parameter versus the classical phenotype. By means of statistical analysis we found that the most prevalent extra-NF1 clinical signs are mental retardation (MR), heart disease (HD) and dysmorphism. Conventional and fiber FISH analysis allowed our pts to be grouped on the basis of deletion type: REP (1.5 Mb del) and BL (del > 1.5 Mb) which distal and proximal boundaries were marked by 271K11-474K4 and 252O24-1J8 respectively. By using bioinformatics we established the deletion gene content: out of 23 genes, one or several of the following genes, CREME9, CENTA2, OMG, EVI2A, KIAA1821, included in both deletion types and of the five genes in the BL deletion, CDK5R1, ZNF207, NJMU-R1, ACCN1, MYO1D, might be implicated in MR. In particular CDK5R1, involved in the development of cerebral cortex, is currently processed for mutation analysis on pts with non X-linked unspecific MR. Only the JJAZ gene appears a suitable candidate for HD; additional genes with unknown function might be identified by expression and bioinformatic studies.