A genotype-first approach identifies high incidence ofNF1pathogenic variants with distinct disease associations

Abstract

AbstractLoss of function variants in theNF1gene cause neurofibromatosis type 1 (NF1), a genetic disorder characterized by complete penetrance, prevalence of 1 in 3,000, characteristic physical exam findings, and a substantially increased risk for malignancy. However, our understanding of the disorder is entirely based on patients ascertained through phenotype-first approaches. Leveraging a genotype-first approach in two large patient cohorts, we demonstrate unexpectedly high prevalence (1 in 450-750) ofNF1pathogenic variants. Half were identified in individuals lacking clinical features of NF1, with many appearing to have post-zygotic mosaicism for the identified variant. Incidentally discovered variants were not associated with classic NF1 features but were associated with an increased incidence of malignancy compared to a control population. Our findings suggest thatNF1pathogenic 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.