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

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 () and Theodore G. Drivas ()
Additional contact information
Anton Safonov: University of Pennsylvania
Tomoki T. Nomakuchi: Children’s Hospital of Philadelphia
Elizabeth Chao: Ambry Genetics
Carrie Horton: Ambry Genetics
Jill S. Dolinsky: Ambry Genetics
Amal Yussuf: Ambry Genetics
Marcy Richardson: Ambry Genetics
Virginia Speare: Ambry Genetics
Shuwei Li: Ambry Genetics
Zoe C. Bogus: University of Pennsylvania
Maria Bonanni: University of Pennsylvania
Anna Raper: University of Pennsylvania
Trust Odia: University of Pennsylvania
Bradley S. Wubbenhorst: University of Pennsylvania
Elsa Faulders: Oberlin College
Elisabeth M. Schuth: University of Pennsylvania
Kate Loranger: Natera Inc.
Jingwen Zhang: Natera Inc.
Carly Bess Scalise: Natera Inc.
Adam ElNaggar: Natera Inc.
Youbao Sha: Natera Inc.
Stephanie A. Felker: Department of Genetics
Jeffrey Weitzel: University of Kansas School of Medicine
Staci Kallish: Children’s Hospital of Philadelphia
Marylyn D. Ritchie: Perelman School of Medicine, University of Pennsylvania
Katherine L. Nathanson: University of Pennsylvania
Theodore G. Drivas: University of Pennsylvania

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57077-1

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