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

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 neurofibromatos

SUBMITTER: Safonov A 

PROVIDER: S-EPMC11962086 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature