A genotype-first approach identifies high incidence of NF1 pathogenic variants with distinct disease associations
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.
Authors
- Anna Raper
- Jill S. Dolinsky (ORCID: https://orcid.org/0000-0002-3854-9539)
- Zoe Bogus
- Youbao Sha
- Stephanie A. Felker (ORCID: https://orcid.org/0000-0002-1809-1524)
- Jeffrey N. Weitzel (ORCID: https://orcid.org/0000-0001-6714-092X)
- Marcy E. Richardson (ORCID: https://orcid.org/0000-0002-4626-4920)
- Anton Safonov (ORCID: https://orcid.org/0000-0002-4100-8071)
- Carolyn Horton (ORCID: https://orcid.org/0000-0001-5186-6208)
- Adam C. ElNaggar (ORCID: https://orcid.org/0000-0003-3409-583X)
- Maria Bonanni
- Amal Yussuf (ORCID: https://orcid.org/0000-0002-7876-2713)
- Bradley Wubbenhorst
- Elizabeth Chao (ORCID: https://orcid.org/0000-0002-4082-371X)
- Tomoki Nomakuchi (ORCID: https://orcid.org/0000-0001-7300-9311)
- Carly Bess Scalise (ORCID: https://orcid.org/0000-0002-7612-7791)
- Trust Odia (ORCID: https://orcid.org/0000-0002-0113-0902)
- Staci Kallish (ORCID: https://orcid.org/0000-0003-2515-2097)
- Katherine L. Nathanson (ORCID: https://orcid.org/0000-0002-6740-0901)
- Theodore G. Drivas (ORCID: https://orcid.org/0000-0002-8717-0111)
- Kate Loranger
- Marylyn DeRiggi Ritchie (ORCID: https://orcid.org/0000-0002-1208-1720)
- Virginia Speare (ORCID: https://orcid.org/0000-0003-4773-9411)
- Jingwen Zhang (ORCID: https://orcid.org/0000-0003-4071-4449)
- Shuwei Li (ORCID: https://orcid.org/0000-0001-7176-1964)
- Elsa Faulders
- Elisabeth M. Schuth
Institutions
- University of the Sciences (US)
- Memorial Sloan Kettering Cancer Center (US)
- Children's Hospital of Philadelphia (US)
- University of Kansas (US)
- University of Alabama at Birmingham (US)
- Natera (United States) (US)
- Translational Therapeutics (United States) (US)
- HudsonAlpha Institute for Biotechnology (US)
- Ambry Genetics (United States) (US)
- Oberlin College (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1038/s41467-025-57077-1
- Citations
- 10
- Primary Topic
- Neurofibromatosis and Schwannoma Cases
- Type
- article
- Field-Weighted Citation Impact
- 13.89