Unraveling novel variants in the NF1 gene and investigating potential therapeutic strategies.

Germline mutations in the NF1 gene disrupt neurofibromin function, leading to autosomal-dominant neurofibromatosis type I (NF1). As a tumor suppressor, neurofibromin negatively regulates the RAS signaling. NF1 presents notable phenotypic variability, progressive symptoms with age, and potential malignant transformation. Early screening, diagnosis, and necessary interventions are essential for improving patient outcomes. Here, sixteen NF1 variants were identified at Henan Provincial People's Hospital. Among them, 75.0% were de novo mutations, and two novel variants, c.547_548delAT p.(Ile183Glnfs*17) and c.4721dupC p.(Thr1574Thrfs*2), were revealed. These two novel variants, located in the RAS-GTPase domain, manifested cutaneous café-au-lait macules at birth; the former even exhibited motor delays. A retrospective analysis of 49 clinical trials over the past 20 years revealed that NF1 therapies predominantly target neurofibromin's GTPase function. Gene therapies aiming to restore neurofibromin by transducing the truncated NF1-GRD gene have been developed but faced pre-clinical challenges, including cloning capacity, transduction efficiency, and immunogenicity caused by gene delivery. Two novel NF1 variants expanded the variation spectrum for the NF1 gene, facilitating the diagnosis, genetic counseling, and clinical management of patients. Therapeutic approaches targeting GTPase and improved gene therapy may dawn a new therapeutic era for NF1.