biostudies-literatureSafonov ANCATS NIH HHSNIDDK NIH HHSNIAID NIH HHSNHGRI NIH HHSNCI NIH HHSNIH HHSNIGMS NIH HHS3121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11962086biostudies-literatureUnknown16(1)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 neurofibromatosNature communicationsA genotype-first approach identifies high incidence of NF1 pathogenic variants with distinct disease associations.PMC11962086OT2 OD026548OT2 OD025315P30 CA008748OT2 OD025337OT2 OD026549T32 GM008638OT2 OD025277OT2 OD025276U24 OD023121T32 HG008961U24 OD023163U2C OD023196OT2 OD026555OT2 OD026554OT2 OD026557OT2 OD026556OT2 OD023205OT2 OD023206R01 CA176785P50 GM115318OT2 OD026551OT2 OD026550OT2 OD026553OT2 OD026552UL1 TR001878R01 CA192393R01 AI116794K08 DK127247U24 OD023176R01 AI077505Odia TYussuf ANathanson KLZhang JSha YBonanni MFelker SAWeitzel JRaper AElNaggar AScalise CBBogus ZCChao ESpeare VRichardson MHorton CRitchie MDFaulders ELoranger KDrivas TGSchuth EMKallish SLi SSafonov ANomakuchi TTDolinsky JSPenn Medicine BioBankWubbenhorst BSfalseA 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 neurofibromatos2025-01-01T00:00:00Z2025 Apr2026-06-01T18:08:57.693Z2025-07-12T03:04:33.65ZS-EPMC119620864016957010.1038/s41467-025-57077-1