Bayesian approach to determining penetrance of pathogenic SDH variants.

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 to their penetrance for disease. We tested this hypothesis using data from two cohorts for succinate dehydrogenase subunits A, B and C () genetic variants associated with hereditary pheochromocytoma/paraganglioma (PC/PGL).

Methods: Two cohorts were 575 unrelated Australian subjects and 1240 unrelated UK subjects, respectively, with PC/PGL in whom genetic testing had been performed. Penetrance of pathogenic variants was calculated by comparing allelic frequencies in cases versus controls from ExAC (removing those variants contributed by The Cancer Genome Atlas).

Results: Pathogenic variants were identified in 106 subjects (18.4%) in cohort 1 and 317 subjects (25.6%) in cohort 2. Of 94 different pathogenic variants from both cohorts (seven in , 75 in and 12 in ), 13 are reported in ExAC (two in , nine in and two in ) accounting for 21% of subjects with variants. Combining data from both cohorts, estimated lifetime disease penetrance was 22.0% (95% CI 15.2% to 30.9%) for variants, 8.3% (95% CI 3.5% to 18.5%) for variants and 1.7% (95% CI 0.8% to 3.8%) for variants.

Conclusion: Pathogenic variants in are more penetrant than those in and . Our findings have important implications for counselling and surveillance of subjects carrying these pathogenic variants.