作者: Diana E Benn , Ying Zhu , Katrina A Andrews , Mathilda Wilding , Emma L Duncan
DOI: 10.1136/JMEDGENET-2018-105427
关键词:
摘要: Background Until recently, determining penetrance required large observational cohort studies. Data from the Exome Aggregate Consortium (ExAC) allows a Bayesian approach to calculate penetrance, in that population frequencies of pathogenic germline variants should be inversely proportional their for disease. We tested this hypothesis using data two cohorts succinate dehydrogenase subunits A, B and C (SDHA–C) genetic associated with hereditary pheochromocytoma/paraganglioma (PC/PGL). Methods Two were 575 unrelated Australian subjects 1240 UK subjects, respectively, PC/PGL whom testing had been performed. Penetrance SDHA–C was calculated by comparing allelic cases versus controls ExAC (removing those contributed The Cancer Genome Atlas). Results Pathogenic identified 106 (18.4%) 1 317 (25.6%) 2. Of 94 different both (seven SDHA, 75 SDHB 12 SDHC), 13 are reported (two nine SDHC) accounting 21% variants. Combining cohorts, estimated lifetime disease 22.0% (95% CI 15.2% 30.9%) variants, 8.3% 3.5% 18.5%) SDHC 1.7% 0.8% 3.8%) SDHA Conclusion more penetrant than SDHA. Our findings have important implications counselling surveillance carrying these