Background: To identify the genetic variants underlying neurofibromatosis type 1 (NF1) and to investigate genotype-phenotype correlations.

Methods: Thirty-three patients from 27 Chinese pedigrees with suspected NF1 phenotypes underwent genetic analysis. The impact of splicing variant on NF1 mRNA processing was determined by cDNA direct sequencing. Additional NF1 patients with detailed clinical and molecular data were extracted from the literature for performing genotype-phenotype correlation analysis.

Results: Genetic analysis identified 24 distinct NF1 variants: nine frameshift, four nonsense, four missense, six splice site, and one exon deletion. Among them, 10 were previously unreported in the literature. A functional study showed that the canonical splicing variant (c.3497-2 A > G) resulted in an in-frame deletion of two amino acids, which may not affect protein function. Finally, 22 variants were classified as pathogenic or likely pathogenic. After evaluation of the clinical data and genetic evidence, the diagnoses of 31 patients from 25 families were confirmed. Genotype-phenotype correlation analysis from the cohort, consisting of 28 patients in this study and 235 published cases, showed that the onset of neurofibromas and bone lesions exhibited an age-dependent association, with 79.8% and 73.8% probability of developing in patients older than 23.5 years or 20.5 years, respectively. No association was found between the location or type of NF1 variants and any specific features.

Conclusions: We comprehensively described the clinical and genetic data of a Chinese NF1 cohort and emphasized the necessity of further functional analysis on splicing variants. Neurofibromas and bone lesions are age-dependent disease complications that exhibit progressive tendencies with increasing age in patients with NF1.