Abstract Neurofibromatosis type 1 (NF1) is a genetic disorder that occurs in about 1:3000 individuals. NF1 is caused by inheritance or de novo mutation/loss of the NF1 gene. Individuals with NF1 are predisposed to numerous manifestations, including the development of plexiform neurofibromas (PNF) and/or optic pathway glioma (OPG). Unlike in more aggressive tumors, apart from changes at NF1, PNF cells do not show many recurrent somatic changes; somatic changes in OPG are rare. Twin studies suggest that germline modifiers of NF1 disease exist, but these remain largely unstudied. Because the identification of NF1 modifiers should enable risk stratification and identification of targetable therapeutic pathways in individuals with NF1 we developed a multidisciplinary team of geneticists, bioinformaticians, statisticians and animal (mouse and fish) modelers. Relying on close collaboration among team members, we will continue identifying genes showing increased numbers of potentially disruptive variants to study. In Aim 1, we will expand our number of individuals with PNF and/or OPG and test if variants are associated with tumor number, tumor burden, or presence of OPG. In Aim 2, we will test candidates in a well-characterized mouse model of plexiform neurofibroma, using the power of mouse genetics. To enhance rapid screening of relevant genes and variants we generated a zebrafish model of PNF and OPG, which will be exploited in Aim 3, by screening for effects of larger numbers of genes predicted to act as NF1 modifiers. The proposed research will provide a basis for precision medicine in NF1. If risk variants in genes are associated with disease severity and/or correlate with tumor burden, then the development of genomic risk assessment tools will be possible at diagnosis.