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Genotype–phenotype correlations of neurofibromatosis type 1: a cross-sectional study from a large Chinese cohort

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Abstract

Background

Neurofibromatosis type 1 (NF1) is a highly heterogeneous autosomal genetic disorder characterized by a broad spectrum of clinical and molecular manifestations. The correlations between genotype and phenotype in NF1 remain elusive. This study aimed to elucidate genotype–phenotype associations in a large Chinese cohort of NF1 patients.

Methods

We included NF1 patients from our center who underwent genetic testing for NF1 variants and systemic examination. Genotype–phenotype correlation analyses were performed, focusing on variation types and involved neurofibromin domains.

Results

A total of 195 patients were enrolled, comprising 105 males and 90 females, with a median age of 18 years. Truncating variants, single amino acid variations, and splicing variants accounted for 139/195 (71.3%), 23/195 (11.8%), and 33/195 (16.9%), respectively. Patients with splicing variants exhibited a significantly higher prevalence of spinal plexiform neurofibromas (spinal PNF) than those with truncating variants (76.4% vs. 51.8%; p = 0.022). Variations affecting the PKC domain were associated with higher rates of cutaneous neurofibromas (CNF) (100% vs. 64.9%, p < 0.001), Lisch nodules (100% vs. 61.2%, p < 0.001), plexiform neurofibromas (PNF) (100% vs. 95.7%, p = 0.009), and psychiatric disorders (11.8% vs. 1.6%, p = 0.042). Patients with mutations in the CSRD had an elevated risk of secondary primary malignancies (11.6% vs. 2.8%, p = 0.015). GRD involvement might enhance the risk of Lisch nodules (76.9% vs. 53.7%, p = 0.044). Variations in the Sec14-PH domain were correlated with a higher rate of CNF (76.8% vs. 58.6%, p = 0.014). Additionally, we found that the p.R1748* variants carry a high risk of malignancy.

Conclusion

Our study suggested some novel genotype–phenotype correlations within a Chinese cohort, providing innovative insights into this complex field that may contribute to genetic counseling, risk stratification, and clinical management for the NF1 population.

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Data Availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank patients and families for their generous collaboration.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82102344; 82172228; 82202470); Shanghai Clinical Research Center of Plastic and Reconstructive Surgery supported by the Science and Technology Commission of Shanghai Municipality (Grant No. 22MC1940300); Innovative research team of high-level local universities in Shanghai (SHSMU-ZDCX20210400); Natural Science Foundation of Shanghai (22ZR1422300); Shanghai Municipal Key Clinical Specialty (shslczdzk00901); the Project of Biobank (YBKA202204) from Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine.

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Author notes

  1. Beiyao Zhu and Tingting Zheng have contributed equally to this work.

Authors and Affiliations

  1. Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China

    Beiyao Zhu, Tingting Zheng, Wei Wang, Yihui Gu, Chengjiang Wei, Qingfeng Li & Zhichao Wang

  2. Neurofibromatosis Type 1 Center and Laboratory for Neurofibromatosis Type 1 Research, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China

    Beiyao Zhu, Tingting Zheng, Wei Wang, Yihui Gu, Chengjiang Wei, Qingfeng Li & Zhichao Wang

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  1. Beiyao Zhu
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Corresponding authors

Correspondence to Qingfeng Li or Zhichao Wang.

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The authors state that there is no conflict of interest.

Ethics approval

This study was approved by the Ethics Committee of Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (SH9H-2019-T163-2) and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All patients/caregivers provided written informed consent prior to study participation.

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Zhu, B., Zheng, T., Wang, W. et al. Genotype–phenotype correlations of neurofibromatosis type 1: a cross-sectional study from a large Chinese cohort. J Neurol 271, 1893–1900 (2024). https://doi.org/10.1007/s00415-023-12127-w

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  • DOI: https://doi.org/10.1007/s00415-023-12127-w

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