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Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types

Journal of Human Genetics volume 65, pages 79–89 (2020)Cite this article

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Abstract

Neurofibromatosis type 1 (NF1) is caused by heterozygous mutation in the NF1 gene. NF1 is one of the most common human genetic diseases. However, the overall genotype–phenotype correlation has not been known, due to a wide spectrum of genotypic and phenotypic heterogeneity. Here we describe the detailed clinical and genetic features of 427 Korean NF1 patients from 389 unrelated families. Long range PCR and sequencing of genomic DNA with multiplex ligation-dependent probe amplification analysis identified 250 different NF1 mutations in 363 families (93%), including 94 novel mutations. With an emphasis on phenotypes requiring medical attention (classified and termed: NF1+), we investigated the correlation of NF1+ and mutation types. NF1+ was more prevalent in patients with truncating/splicing mutations and large deletions than in those with missense mutations (59.6%, 64.3% vs. 36.6%, p = 0.001). This difference was especially significant in the patients younger than age 19 years. The number of items in NF1+ was a higher in the former groups (0.95 ± 0.06, 1.18 ± 0.20 vs. 0.56 ± 0.10, p = 0.002). These results suggest that mutation types are associated not only with higher prevalence of severe phenotypes in NF1 but also with their earlier onset.

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Acknowledgements

We deeply appreciate the patients and their families for participating in this study.

Funding

This research was supported in part by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (NRF-2015K1A4A3046807 and NRF-2018M3A9H1078335).

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Authors and Affiliations

  1. Department of Pediatrics, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Republic of Korea

    Eungu Kang

  2. Department of Pediatrics, Gangneung Asan Hospital, Gangneung, Republic of Korea

    Yoon-Myung Kim

  3. Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, 88, Olympic-ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea

    Go Hun Seo, Arum Oh, Heyry Kim, Han-Wook Yoo & Beom Hee Lee

  4. Department of Radiology and Research Institute of Radiology, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Hee Mang Yoon

  5. Departments of Neurosurgery, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Young-Shin Ra

  6. Department of Plastic Surgery, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Eun Key Kim

  7. Asan Institute for Life Sciences, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Sun-Hee Heo

  8. Medical Genetics Center, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Gu-Hwan Kim, Han-Wook Yoo & Beom Hee Lee

  9. Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA

    Mark J. Osborn & Jakub Tolar

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  1. Eungu Kang
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Kang, E., Kim, YM., Seo, G.H. et al. Phenotype categorization of neurofibromatosis type I and correlation to NF1 mutation types. J Hum Genet 65, 79–89 (2020). https://doi.org/10.1038/s10038-019-0695-0

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