Article Text
Abstract
Background Birt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the FLCN gene. Patients with BHD syndrome have an increased risk of fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma. There is debate regarding whether colonic polyps should be added to the criteria. Previous risk estimates have mostly been based on small clinical case series.
Methods A comprehensive review was conducted to identify studies that had recruited families carrying pathogenic or likely pathogenic variants in FLCN. Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers of FLCN pathogenic variants.
Results Our final dataset contained 204 families that were informative for at least one manifestation of BHD (67 families informative for skin manifestations, 63 for lung, 88 for renal carcinoma and 29 for polyps). By age 70 years, male carriers of the FLCN variant have an estimated 19% (95% CI 12% to 31%) risk of renal tumours, 87% (95% CI 80% to 92%) of lung involvement and 87% (95% CI 78% to 93%) of skin lesions, while female carriers had an estimated 21% (95% CI 13% to 32%) risk of renal tumours, 82% (95% CI 73% to 88%) of lung involvement and 78% (95% CI 67% to 85%) of skin lesions. The cumulative risk of colonic polyps by age 70 years old was 21% (95% CI 8% to 45%) for male carriers and 32% (95% CI 16% to 53%) for female carriers.
Conclusions These updated penetrance estimates, based on a large number of families, are important for the genetic counselling and clinical management of BHD syndrome.
- Gene Expression
- Genetic Predisposition to Disease
- Genetic Research
- Human Genetics
Data availability statement
Data are available upon reasonable request. Data are available upon reasonable request and with permission from the relevant authors.
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Data availability statement
Data are available upon reasonable request. Data are available upon reasonable request and with permission from the relevant authors.
Footnotes
Correction notice The article has been corrected since it was published online first (author's name).
Collaborators Gianluca Severi, Ingrid Winship, Fiona Bruinsma, Eamonn Maher, Tracy Dudding, Kathy Tucker, Todd Edwards, Min-Han Tan, Stephen Chanock, Marsten Linehan, Mark Jenkins, Maurice van Steensel and Ian Tomlinson.
Contributors FJB is the guarantor for the study, accepting full responsibility for the conduct of the study, had access to the data and controlled the decision to publish. FJB and IMW were responsible for the design and conduct of the study. The I-CONFIRM genetic susceptibility working group and KT provided advice on the design of the study and clinical context. DB, JW and LCG undertook data extraction, assisted in the analysis and in the writing of the manuscript. JGD and AKW undertook the analysis and assisted with the writing of the manuscript. ERM provided the data, advised on the design and clinical aspects of the study and in writing the manuscript. PA, DA, NB, MDL, DBE, MF, GG, MG, A-MG, TVOH, ACH, PCJ, AL, DL, NML, VL, ML, AM, FHM, GM, JSP, RHJ, ECS, OKS, ST, DT, IvdB, LvR, MvS, TZ and MZ provided data and assisted with the interpretation of the findings and writing of the manuscript.
Funding This work was supported by Cancer Council Victoria via salary support for FJB. ERM acknowledges support from the National Institute for Health Research (NIHR) (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre, BRC-1215–20014). The University of Cambridge received salary support in respect of ERM from the NHS in the East of England through the Clinical Academic Reserve.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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