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Bayesian approach to determining penetrance of pathogenic SDH variants.

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cam.issuedOnline2018-09-10
dc.contributor.authorBenn, Diana E
dc.contributor.authorZhu, Ying
dc.contributor.authorAndrews, Katrina A
dc.contributor.authorWilding, Mathilda
dc.contributor.authorDuncan, Emma L
dc.contributor.authorDwight, Trisha
dc.contributor.authorTothill, Richard W
dc.contributor.authorBurgess, John
dc.contributor.authorCrook, Ashley
dc.contributor.authorGill, Anthony J
dc.contributor.authorHicks, Rodney J
dc.contributor.authorKim, Edward
dc.contributor.authorLuxford, Catherine
dc.contributor.authorMarfan, Helen
dc.contributor.authorRichardson, Anne Louise
dc.contributor.authorRobinson, Bruce
dc.contributor.authorSchlosberg, Arran
dc.contributor.authorSusman, Rachel
dc.contributor.authorTacon, Lyndal
dc.contributor.authorTrainer, Alison
dc.contributor.authorTucker, Katherine
dc.contributor.authorMaher, Eamonn R
dc.contributor.authorField, Michael
dc.contributor.authorClifton-Bligh, Roderick J
dc.contributor.orcidMaher, Eamonn R [0000-0002-6226-6918]
dc.date.accessioned2018-11-17T00:31:52Z
dc.date.available2018-11-17T00:31:52Z
dc.date.issued2018-11
dc.description.abstractBACKGROUND: 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.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.32750
dc.identifier.eissn1468-6244
dc.identifier.issn0022-2593
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285384
dc.languageeng
dc.language.isoeng
dc.publisherBMJ
dc.publisher.urlhttp://dx.doi.org/10.1136/jmedgenet-2018-105427
dc.rightsAttribution-NonCommercial 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/
dc.subjectparaganglioma
dc.subjectpathogenic variant
dc.subjectpenetrance
dc.subjectpheochromocytoma
dc.subjectsuccinate dehydrogenase
dc.subjectAlgorithms
dc.subjectAlleles
dc.subjectAustralia
dc.subjectBayes Theorem
dc.subjectGenetic Association Studies
dc.subjectGenetic Predisposition to Disease
dc.subjectGenetic Variation
dc.subjectGenotype
dc.subjectHumans
dc.subjectIsoenzymes
dc.subjectModels, Genetic
dc.subjectPenetrance
dc.subjectPhenotype
dc.subjectSuccinate Dehydrogenase
dc.subjectUnited Kingdom
dc.titleBayesian approach to determining penetrance of pathogenic SDH variants.
dc.typeArticle
dcterms.dateAccepted2018-08-20
prism.endingPage734
prism.issueIdentifier11
prism.publicationDate2018
prism.publicationNameJ Med Genet
prism.startingPage729
prism.volume55
pubs.funder-project-idEuropean Research Council (323004)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0616-10035)
rioxxterms.licenseref.startdate2018-11
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1136/jmedgenet-2018-105427

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