A genotype-first approach identifies high incidence of NF1 pathogenic variants with distinct disease associations
Anton Safonov, Tomoki Nomakuchi, Elizabeth Chao, Carolyn Horton, Jill S. Dolinsky, Amal Yussuf, Marcy E. Richardson, Virginia Speare, Shuwei Li, Zoe Bogus, Maria Bonanni, Anna Raper, Trust Odia, Bradley Wubbenhorst, Elsa Faulders, Elisabeth M. Schuth, Kate Loranger, Jingwen Zhang, Carly Bess Scalise, Adam C. ElNaggar, Youbao Sha, Stephanie A. Felker, Jeffrey N. Weitzel, Staci Kallish, Marylyn D. Ritchie, Penn Medicine BioBank, Katherine L. Nathanson, Theodore G. Drivas
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. Our current understanding of neurofibromatosis type 1 (NF1) is based on patients ascertained through phenotype-first approaches, which estimate a low prevalence at 1 in 3,000. Here, the authors leverage a genotype-first approach in multiple large patient cohorts to demonstrate an unexpectedly high prevalence (1 in 1,286) of NF1 pathogenic variants with distinct disease associations.