Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype-Phenotype Correlations in A Large Independent Cohort

Abstract

The occurrence of optic pathway gliomas (OPGs) in children with neurofibromatosis type 1 (NF1) still raises many questions regarding screening and surveillance because of the lack of robust prognostic factors. Recent studies of an overall cohort of 381 patients have suggested that the genotype may be the main determinant of the development of OPG, with the risk being higher in patients harbouring NF1 mutations in the 5' tertile and the cysteine/serine-rich domain. In an attempt to confirm this hypothesis, we used strict criteria to select a large independent cohort of 309 NF1 patients with defined constitutional NF1 mutations and appropriate brain images (255 directly enrolled and 54 as a result of a literature search). One hundred and thirty-two patients had OPG and 177 did not. The association of the position (tertiles and functional domains) and type of NF1 mutation with the development of OPG was analysed using the χ2 test and Fisher's exact probability test; odds ratios (ORs) with 95% confidence intervals were calculated, and Bonferroni's correction for multiple comparisons was applied; multiple logistic regression was also used to study genotype-phenotype associations further. Our findings show no significant correlation between the site/type of NF1 mutation and the risk of OPG, and thus do not support the hypothesis that certain constitutional mutations provide prognostic information in this regard. In addition, we combined our cohort with a previously described cohort of 381 patients for a total of 690 patients and statistically re-analysed the results. The re-analysis confirmed that there were no correlations between the site (tertile and domain) and the risk of OPG, thus further strengthening our conclusions.

Keywords: Key words: neurofibromatosis type 1; NF1 gene; genotype–phenotype correlations; optic pathway glioma.

Figure 1

Schematic representation of the tertiles of the neurofibromatosis type 1 (NF1) gene and the domains of neurofibromin. CSRD, cysteine/serine-rich domain; TBD, tubulin-binding domain; GRD, GTPase activating protein-related domain; PH, pleckstrin homology-like domain; Sec-14, Sec14-like domain; HLR, HEAT-like repeat regions; NLS, nuclear localisation signal region; CTD, C-terminal domain; SBR, syndecan-binding region.

Figure 2

Distribution of NFI gene mutations by tertile and domain in the optic pathway glioma (OPG) group. The horizontal bars indicate two OPG patients with a large deletion involving more than one exon. The vertical red lines indicate the limits of the tertiles.

Figure 3

Distribution of NF1 gene mutations by tertile and domain in the non-OPG group. The horizontal bars indicate two OPG patients with a large deletion involving more than one exon. The vertical red lines indicate the limits of the tertiles.