Refined genotype-phenotype correlations in neurofibromatosis type 1 patients with NF1 point variants

Abstract

Background: Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders. NF1 is caused by dominant loss-of-function pathogenic variants (PVs) of the tumour-suppressor gene NF1, which encodes neurofibromin, a negative regulator of rat sarcoma proteins. NF1 is an autosomal dominant disorder with complete penetrance, but a highly variable expression. Identification of genotype-phenotype correlations is challenging because of the wide clinical variability, the progressive nature of the disorder and the extreme diversity of the mutation spectrum. Only a few NF1 point variants have been associated with a specific phenotype in NF1 patients.

Methods: We investigated a large, well-phenotyped NF1 cohort.

Results: We report analyses of genotype-phenotype correlations in 112 NF1 patients with specific NF1 point variants: p.Arg1809 missense variants were associated with a mild form of NF1 (n=24), while a more severe phenotype was associated with codons 844-848 (n=27), p.Arg1276 (n=25) and p.Lys1423 (n=35) missense variants. We describe a new correlation for p.Arg1204 missense variants (n=11), with no neurofibroma observed in patients. Functional studies will be critical for drawing conclusions on the potential hypomorphic or dominant-negative effects of these variants.

Conclusion: The current data confirms several genotype-phenotype correlations in NF1, which may be relevant to the management and surveillance of NF1 patients with specific NF1 PVs.

Keywords: Genetic Diseases, Inborn.

Figure 1. Location of NF1 gene point variants associated with a specific form of the disease. N indicates the number of patients described in each study, with the number of families involved in square brackets. Arrows indicate symptoms significantly more frequently (↗) or more rarely (↘) observed in the different groups, compared with the overall population of NF1 patients, at the 5% threshold. Numbers indicate the position of neurofibromin amino acids. CALS, café-au-lait spots; cNFs, cutaneous neurofibromas; CSRD, cysteine/serine-rich domain; CTD, C-terminal domain; CV, cardiovascular; GRD, rat sarcoma-GAP (GTPase-activating protein)-related domain; LNs: Lisch nodules; LRD, leucine-rich domain; NFs, neurofibromas; NLS, nuclear localisation signal; OPGs, optic pathway gliomas; pNFs, plexiform neurofibromas; SBR, syndecan-binding region; Sec14-PH, Saccharomyces cerevisiae phosphatidylinositol transfer protein-like domain–pleckstrin homology-like domain; TBD, tubulin-binding domain.

Figure 2. Radar plot of the frequency of the main clinical features in the present cohort and the ‘classic’ NF1 cohort. Frequency of features with a white circle (°) or an asterisk (*) significantly differs between the two cohorts, respectively, only before or after correction for multiple testing with the Benjamini-Hochberg procedure. CALS, café-au-lait spots; cNFs, cutaneous neurofibromas; NF1, neurofibromatosis type 1; OPGs, optic pathway gliomas; pNFs, plexiform neurofibromas; scNFs, subcutaneous neurofibromas.