The Role of Artificial Intelligence in Identifying NF1 Gene Variants and Improving Diagnosis

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1 gene, typically diagnosed during early childhood and characterized by significant phenotypic heterogeneity. Despite advancements in next-generation sequencing (NGS), the diagnostic process remains challenging due to the gene's complexity, high mutational burden, and frequent identification of variants of uncertain significance (VUS). This review explores the emerging role of artificial intelligence (AI) in enhancing NF1 variant detection, classification, and interpretation. A systematic literature search was conducted across PubMed, IEEE Xplore, Google Scholar, and ResearchGate to identify recent studies applying AI technologies to NF1 genetic analysis, focusing on variant interpretation, structural modeling, tumor classification, and therapeutic prediction. The review highlights the application of AI-based tools such as VEST3, REVEL, ClinPred, and NF1-specific models like DITTO and RENOVO-NF1, which have demonstrated improved accuracy in classifying missense variants and reclassifying VUS. Structural modeling platforms like AlphaFold contribute further insights into the impact of NF1 mutations on neurofibromin structure and function. In addition, deep learning models, such as LTC neural networks, support tumor classification and therapeutic outcome prediction, particularly in NF1-associated complications like congenital pseudarthrosis of the tibia (CPT). The integration of AI methodologies offers substantial potential to improve diagnostic precision, enable early intervention, and support personalized medicine approaches. However, key challenges remain, including algorithmic bias, limited data diversity, and the need for functional validation. Ongoing refinement and clinical validation of these tools are essential to ensure their effective implementation and equitable use in NF1 diagnostics.

Keywords: AI; CPT; NF1; NGS; VUS; children; gene; phenotype; tumors.

Figure 1

Genotype—phenotype correlation in NF1 and role of NGS and AI in precision medicine.