Bayesian approach to determining penetrance of pathogenic SDH variants
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Description
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.
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ID Code: | 124022 | ||
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Item Type: | Contribution to Journal (Journal Article) | ||
Refereed: | Yes | ||
ORCID iD: |
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Measurements or Duration: | 6 pages | ||
Keywords: | paraganglioma, pathogenic variant, penetrance, pheochromocytoma, succinate dehydrogenase | ||
DOI: | 10.1136/jmedgenet-2018-105427 | ||
ISSN: | 1468-6244 | ||
Pure ID: | 33388218 | ||
Divisions: | Past > QUT Faculties & Divisions > Faculty of Health Past > Institutes > Institute of Health and Biomedical Innovation |
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Copyright Owner: | Consult author(s) regarding copyright matters | ||
Copyright Statement: | This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the document is available under a Creative Commons License (or other specified license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recognise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to qut.copyright@qut.edu.au | ||
Deposited On: | 02 Jan 2019 06:08 | ||
Last Modified: | 02 Apr 2024 20:42 |
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