A genotype-first approach identifies high incidence of NF1 pathogenic variants with distinct disease associations Journal Article
| Authors: | Safonov, A.; Nomakuchi, T. T.; Chao, E.; Horton, C.; Dolinsky, J. S.; Yussuf, A.; Richardson, M.; Speare, V.; Li, S.; Bogus, Z. C.; Bonanni, M.; Raper, A.; Odia, T.; Wubbenhorst, B. S.; Faulders, E.; Schuth, E. M.; Loranger, K.; Zhang, J.; Scalise, C. B.; ElNaggar, A.; Sha, Y.; Felker, S. A.; Weitzel, J.; Kallish, S.; Ritchie, M. D.; Nathanson, K. L.; Drivas, T. G. |
| Article Title: | 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 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. © The Author(s) 2025. |
| Keywords: | adolescent; adult; child; preschool child; aged; child, preschool; middle aged; young adult; major clinical study; genetics; clinical feature; cancer risk; pancreas cancer; neoplasm; neoplasms; colorectal cancer; phenotype; neurofibromatosis; genetic predisposition to disease; neurofibromatosis 1; ovary cancer; breast cancer; gene expression; incidence; prevalence; cohort analysis; genotype; risk assessment; sarcoma; hematologic malignancy; comorbidity; neurofibromin; neurofibromin 1; physical examination; genetic disorder; epidemiology; genetic predisposition; penetrance; mosaicism; neurofibromatosis type 1; genetic association studies; disease incidence; adrenal cancer; monogenic disorder; human epidermal growth factor receptor 2 positive breast cancer; humans; human; male; female; article; genetic association study; central nervous system cancer; uk biobank; nf1 protein, human |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-04-01 |
| Start Page: | 3121 |
| Language: | English |
| DOI: | 10.1038/s41467-025-57077-1 |
| PUBMED: | 40169570 |
| PROVIDER: | scopus |
| PMCID: | PMC11962086 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
