1. The NF1 pathogenic mutational spectrum and variant interpretation from 134,187 individuals in a population database
- Author
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DeVon N. Hunter-Schlichting, Lauren J. Mills, Erin L. Crowgey, Gregory B. Marsh, Christopher L. Moertel, and Erin L. Marcotte
- Abstract
Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. NF1 is a large tumor suppressor gene and related disorders are characterized by several major features, age of onset, variability of severity and occurrence of complications. Pathogenic variants are associated with increased risks of rare and common neoplasms and a large array of clinical phenotypes in adults and children. This study compared two variant interpretation approaches: a publicly available population schematic and the clinical gold standard of the ACMG criteria. The population utilized 134,187 individuals who were ascertained to not have cancer in a cancer study from gnomAD (v2.1). A total of 103 pathogenic and 20 likely pathogenic short variants were identified in the population approach and 6 pathogenic and 13 likely pathogenic were identified through the ACMG criteria. Fifty pathogenic variants were identified to have been previously published with associated clinical phenotypes. Malignant tumors and hematologic malignancies such as rhabdomyosarcomas, malignant peripheral nerve sheath tumors, Watson Syndrome, Familial Spinal NF1, optic glioma and JMML were the most severe phenotypes identified. The recent inclusion of genetic testing in the clinical diagnosis of NF1 syndrome increases the need to fully understand the full scope of genotype-phenotype correlations associated with pathogenic NF1 variants across ethnicities. The ascertainment of individuals with germline pathogenic NF1 variants in this analysis highlights cases with potentially increased personal adult-onset cancer risk and unknown reproductive risk of hereditary juvenile-onset cancers. more...
- Published
- 2022
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