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. 2018 Nov;55(11):729-734.
doi: 10.1136/jmedgenet-2018-105427. Epub 2018 Sep 10.

Bayesian approach to determining penetrance of pathogenic SDH variants

Diana E Benn  1   2 , Ying Zhu  1   2   3 , Katrina A Andrews  4 , Mathilda Wilding  3 , Emma L Duncan  5   6   7 , Trisha Dwight  1   2 , Richard W Tothill  8   9 , John Burgess  10 , Ashley Crook  3 , Anthony J Gill  2   11 , Rodney J Hicks  8   9 , Edward Kim  1   2 , Catherine Luxford  1 , Helen Marfan  12 , Anne Louise Richardson  1 , Bruce Robinson  1   2   13 , Arran Schlosberg  2 , Rachel Susman  12 , Lyndal Tacon  1   13   2 , Alison Trainer  8   9 , Katherine Tucker  14 , Eamonn R Maher  4 , Michael Field  3 , Roderick J Clifton-Bligh  1   13   2
Affiliations

Bayesian approach to determining penetrance of pathogenic SDH variants

Diana E Benn et al. J Med Genet. 2018 Nov.

Abstract

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 (SDHA-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 SDHA-C variants was calculated by comparing allelic frequencies in cases versus controls from ExAC (removing those variants contributed by The Cancer Genome Atlas).

Results: Pathogenic SDHA-C 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 SDHA, 75 in SDHB and 12 in SDHC), 13 are reported in ExAC (two in SDHA, nine in SDHB and two in SDHC) accounting for 21% of subjects with SDHA-C variants. Combining data from both cohorts, estimated lifetime disease penetrance was 22.0% (95% CI 15.2% to 30.9%) for SDHB variants, 8.3% (95% CI 3.5% to 18.5%) for SDHC variants and 1.7% (95% CI 0.8% to 3.8%) for SDHA variants.

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

Keywords: paraganglioma; pathogenic variant; penetrance; pheochromocytoma; succinate dehydrogenase.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Estimated lifetime penetrance of pheochromocytoma/paraganglioma (PC/PGL) in subjects heterozygous for genetic variants in succinate dehydrogenase subunits A, B and C (SDHA, SDHB and SDHC) from cohorts 1 and 2 combined. The algorithm used to calculate these estimates is based on Minikel et al and takes into account allelic frequencies in cases versus Exome Aggregate Consortium (ExAC) controls and estimated population prevalence of these disorders.
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