Clinical characteristics and variant spectrum of NF1 in Chinese patients with neurofibromatosis type 1: a cross-sectional study

Abstract Background Neurofibromatosis type 1 (NF1) is a rare autosomal dominant multisystem disorder caused by NF1 gene variants. Although NF1 shows marked clinical and genetic heterogeneity, large Chinese cohorts integrating clinical features, NF1 variant spectrum, and external variant contextualization remain limited. Methods We conducted a cross-sectional study of 847 clinically confirmed Chinese patients with NF1 to characterize demographic features, clinical manifestations, DNB-defined severity, and NF1 variant spectrum. Whole-exome sequencing was performed in 211 patients. Transcript-level variant distribution was assessed using a 500-bp sliding-window approach and further contextualized using ClinVar-derived NF1 variant data. Results Among 847 patients, the median age was 23 years, 27.5% had a family history of NF1, and more than 90% were younger than 40 years. Café-au-lait macules, neurofibromas, and plexiform neurofibromas were observed in 98.3%, 70.7%, and 20.9% of patients, respectively. Younger age, lower neurofibroma burden, and absence of learning difficulties were associated with DNB-defined mild classification. Among 211 genetically tested patients, pathogenic/likely pathogenic NF1 variants were identified in 182 patients, 11 carried NF1 variants of uncertain significance, and 18 had no reportable NF1 variant. In total, 152 distinct NF1 variants were identified, including 45 novel sites. Transcript-level analysis showed regional variation in reportable nucleotide-level NF1 variants, with relatively higher variant density around exons 10–15 and 44–49. Comparison with ClinVar pathogenic/likely pathogenic NF1 variants showed no significant window-level difference after multiple-testing correction. Conclusions This cross-sectional study summarizes the clinical and genetic features of Chinese patients with NF1 and expands the known NF1 variant spectrum in this population. Transcript-level analysis showed regional variation in reportable NF1 variants, broadly paralleling the ClinVar pathogenic/likely pathogenic NF1 variant distribution. These findings provide a basis for future longitudinal studies to validate clinically meaningful genotype–phenotype relationships in NF1.