Abstract
Neurofibromatosis type I is a rare neurocutaneous syndrome resulting from loss-of-function mutations of NF1. The present study sought to determine a correlation between mutation regions on NF1 and the risk of developing optic pathway glioma (OPG) in patients with neurofibromatosis type I. A total of 215 patients with neurofibromatosis type I, from our clinic or previously reported literature, were included in the study after applying strict inclusion and exclusion criteria. Of these, 100 patients with OPG were classified into the OPG group and 115 patients without OPG (aged ≥ 10 years) were assigned to the Non-OPG group. Correlation between different mutation regions and risk of OPG was analyzed. The mutation clustering in the 5′ tertile of NF1 was not significantly different between OPG and Non-OPG groups (P = 0.131). Interestingly, patients with mutations in the cysteine/serine-rich domain of NF1 had a higher risk of developing OPG than patients with mutations in other regions [P = 0.019, adjusted odds ratio (OR) = 2.587, 95% confidence interval (CI) = 1.167–5.736], whereas those in the HEAT-like repeat region had a lower risk (P = 0.036, adjusted OR = 0.396, 95% CI = 0.166–0.942). This study confirms a new correlation between NF1 genotype and OPG phenotype in patients with neurofibromatosis type I, and provides novel insights into molecular functions of neurofibromin.
Highlights
Neurofibromatosis type I (MIM entry: 162200) is a rare disease with autosomal dominant inheritance that belongs to a neurocutaneous syndrome characterized by café-au-lait spots, skin freckling, neurofibroma, Lisch nodules, and optic pathway glioma (OPG) (Jett and Friedman, 2010)
Exclusion criteria included: (1) inconclusive radiological diagnosis of OPG; (2) wrong assessment of gene mutations, due to cDNA changes not conforming to predicted amino acid alterations or the original cDNA base in the reported position not conforming to the corresponding base in the reference sequence; (3) existence of two variants of NF1 in a patient for which the pathogenic one could not be determined according to present evidence; (4) patients in a study which only focused on a certain point mutation, because these patients were selected artificially
Having assembled a large sample using strict inclusion criteria, we verified whether mutation clustering conformed to that in previous studies by comparing the number of patients from both groups, whose mutations were located in different tertiles (Sharif et al, 2011; Bolcekova et al, 2013; Hutter et al, 2016)
Summary
Neurofibromatosis type I (MIM entry: 162200) is a rare disease with autosomal dominant inheritance that belongs to a neurocutaneous syndrome characterized by café-au-lait spots, skin freckling, neurofibroma, Lisch nodules, and optic pathway glioma (OPG) (Jett and Friedman, 2010). Neurofibromatosis type I results from loss-of-function mutations of the tumor suppressor NF1 gene encoding neurofibromin (Trovó-Marqui and Tajara, 2006). The NF1 sequence has been known for nearly 30 years, the correlation between genotype and phenotype in neurofibromatosis type I remains poorly. This is largely due to low incidence, the considerable length of NF1, diffused distribution of mutations, and the agedependent variability of manifestations (Wallace et al, 1990). The few published genotype–phenotype correlations have indicated a severe phenotype in patients with whole-gene deletion and the absence of cutaneous neurofibroma in patients with a 3-bp inframe deletion (c.2970–2972 delAAT) or missense mutation (p.Arg1809Cys) (Cnossen et al, 1997; Upadhyaya et al, 2007; Mautner et al, 2010; Pinna et al, 2014)
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