Neurofibromatosis 1 (NF1) is a genetic disorder caused by germline mutations in the NF1 gene, manifested by various tissues proliferation, including plexiform neurofibromas. Even though somatic loss of NF1 is a common molecular mechanism, plexiform neurofibroma phenotype, varies from indolent to locally aggressive, suggesting contribution of additional modifiers. We investigated the development of a life-threatening, rapidly progressive plexiform neurofibroma in a 9-month-old female infant with NF1. Germline and somatic genetic analysis was conducted through whole exome sequencing and chromosomal microarray analysis. Site-directed mutagenesis, Lentiviral transduction, cell culture and western blot were used for functional studies. In addition to a de-novo pathogenic variant in the NF1 gene, the proband harbored a known pathogenic variant in another Rasopathy gene, LZTR1 which was inherited from the patient’s mother. Further somatic analysis revealed NF1 loss of heterozygosity and a variant in the gene encoding a G Protein Coupled Receptor, GNAZ. Cells expressing the mutant GNAZ exhibited increased ERK activation compared to those expressing the wild type GNAZ. We suggest that variants in NF1, LZRT1, and GNAZ act synergistically in our patient, leading to activation of the MAPK pathway and contributing to the severity of her plexiform neurofibromatosis. This case study demonstrates the power of next generation sequencing in understanding the patho-mechanisms of complex cases, and contributes to the knowledge of germline and somatic non-NF1 variants affecting the clinical phenotype.

ESDR175 - Concomitant LZTR1 and NF1 mutations contribute to the diversity of the Neurofibromatosis 1 phenotypic spectrum

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING