# Genetic analysis of 25 Chinese pedigrees with neurofibromatosis type 1 and genotype-phenotype study from an extended cohort

## TL;DR

This study analyzed 25 Chinese families with neurofibromatosis type 1, identifying new genetic variants and showing that certain complications worsen with age.

## Contribution

The study reports 10 previously unreported NF1 variants and provides age-dependent insights into disease progression.

## Key findings

- 24 distinct NF1 variants were identified, including 10 not previously reported.
- Neurofibromas and bone lesions are more likely to develop in patients over 20.5 and 23.5 years old.
- Splicing variant c.3497–2 A > G causes an in-frame deletion but may not affect protein function.

## Abstract

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

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.

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.

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.

The online version contains supplementary material available at 10.1186/s13023-025-03807-z.