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<p>Loss of function variants in the <i>NF1</i> gene cause neurofibromatosis type 1, a genetic disorder characterized by complete penetrance, characteristic physical exam findings, and a substantially increased risk for malignancy. However, our understanding of the disorder is based on patients ascertained through phenotype-first approaches, which estimate prevalence at 1 in 3000. Leveraging a genotype-first approach in multiple large patient cohorts including over one million individuals, we demonstrate an unexpectedly high prevalence (1 in 1,286) of <i>NF1</i> pathogenic variants. Half are identified in individuals lacking clinical features of NF1, with many appearing to have post-zygotic mosaicism for the identified variant. Incidentally discovered variants are not associated with classic neurofibromatosis features but are associated with an increased incidence of malignancy compared to control populations. Our findings suggest that <i>NF1</i> pathogenic variants are substantially more common than previously thought, often characterized by somatic mosaicism and reduced penetrance, and are important contributors to cancer risk in the general population.</p>

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A genotype-first approach identifies high incidence of NF1 pathogenic variants with distinct disease associations

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月1日

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  • Anton Safonov,
  • Tomoki T. Nomakuchi,
  • Elizabeth Chao,
  • Carrie Horton,
  • Jill S. Dolinsky,
  • Amal Yussuf,
  • Marcy Richardson,
  • Virginia Speare,
  • Shuwei Li,
  • Zoe C. Bogus,
  • Maria Bonanni,
  • Anna Raper,
  • Trust Odia,
  • Bradley S. Wubbenhorst,
  • Elsa Faulders,
  • Elisabeth M. Schuth,
  • Kate Loranger,
  • Jingwen Zhang,
  • Carly Bess Scalise,
  • Adam ElNaggar,
  • Youbao Sha,
  • Stephanie A. Felker,
  • Jeffrey Weitzel,
  • Staci Kallish,
  • Marylyn D. Ritchie,
  • Katherine L. Nathanson,
  • Theodore G. Drivas

摘要

Loss of function variants in the NF1 gene cause neurofibromatosis type 1, a genetic disorder characterized by complete penetrance, characteristic physical exam findings, and a substantially increased risk for malignancy. However, our understanding of the disorder is based on patients ascertained through phenotype-first approaches, which estimate prevalence at 1 in 3000. Leveraging a genotype-first approach in multiple large patient cohorts including over one million individuals, we demonstrate an unexpectedly high prevalence (1 in 1,286) of NF1 pathogenic variants. Half are identified in individuals lacking clinical features of NF1, with many appearing to have post-zygotic mosaicism for the identified variant. Incidentally discovered variants are not associated with classic neurofibromatosis features but are associated with an increased incidence of malignancy compared to control populations. Our findings suggest that NF1 pathogenic variants are substantially more common than previously thought, often characterized by somatic mosaicism and reduced penetrance, and are important contributors to cancer risk in the general population.