The spectrum of pathogenic NF1 variants in participants enrolling on clinical trials of MEK inhibitors for plexiform neurofibroma.

Patients with neurofibromatosis type 1 (NF1) enrolled on interventional clinical trials of a mitogen activated protein kinase (MEK) inhibitor for a plexiform neurofibroma (PN) are required to have inoperable, progressive and/or symptomatic tumor as per protocol inclusion criteria. Thus, the represented germline pathogenic NF1 variants of these clinical trial participants may correlate with increased risk for symptomatic and/or progressive PN. However, the spectrum of pathogenic NF1 variants of participants enrolled on interventional clinical trials has not been previously described. Herein, we report 39 individuals with a diagnosis of NF1 per the National Institutes of Health consensus criteria who received treatment with a MEK inhibitor through a clinical trial for a morbid and/or progressive PN. Truncating variants were the most common variant (N = 14; 36.8%), followed by frameshift (N = 10; 26.3%) and canonical splice/intronic (N = 7; 18.4%); only 1 participant had a NF1 microdeletion (2.5%). Three variants were noted to be recurrent in the study population (c.6789_6792del (p.Tyr2264Thrfs*5), c.4537 C > T (p.Arg1513*), and c.3826 C > T (p.Arg1276*)); there were no related study participants. There was no significant difference in rates of PN response to MEK inhibition across NF1 variant subtype (P = 0.616). In summary, the reported NF1 germline variants may represent those associated with an increased likelihood of symptomatic PN, however sample size limits inference regarding correlation. Contribution of this study’s findings to the literature may support future development of more accurate risk stratification for PN in individuals with NF1.