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A7467 - Rethinking the Epidemiology of Birt-Hogg-Dubé: A Genetics-Based Approach
Author Block: H. Dong, G. R. Washko, D. Qiao, M. H. Cho, B. A. Raby; Brigham and Women's Hospital, Boston, MA, United States.
Introduction: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant genetic disorder resulting from loss-of-function (LOF) mutations of the FLCN gene and presents with multiple lung cysts, recurrent pneumothorax, cutaneous fibrofolliculomas and renal tumors. There are only approximately 600 reported BHD families to date. Given that BHD usually presents in adulthood with nonspecific findings, we suspect that the true prevalence is much higher. This study attempts to estimate the prevalence of BHD variants using available genetic datasets. Methods: Using FLCN gene DNA sequence data from the Genome Aggregation Database (gnomAD), we filtered for variants predicted to lead to LOF mutations. The resulting variants and their allele counts were used to estimate the genetic prevalence. We also reviewed available exome sequence and imaging data from 1008 participants from the COPDGene study to assess the prevalence and phenotypic relevance of FLCN variation. Chest computed tomography scans of 19 subjects with FLCN missense single nucleotide variants (SNVs) were compared to those from 95 matched controls for the presence of parenchymal lung cysts. Results: Within the gnomAD database (N=138,592), there were 19 LOF variants meeting our criteria for pathogenic variation, with a total allele count of 38, resulting in an estimated carrier frequency of 0.00028 (0.00019-0.00038). The most common LOF variant was the protein-truncating single base insertion c.1285dupC (p.His429ProfsTer27), observed in 34.2% of carriers. In the COPDGene study, though no LOF variants were found among the 1008 subjects, 14 missense SNVs were identified in 19 subjects. Lung cysts were present in 8 of these subjects (42%) and in 18 of 95 (18.9%) matched subjects without FLCN SNVs (OR 3.1, 95% CI 1.03-9.56, p=0.04). Out of the 14 SNVs, 4 were predicted to be probably pathogenic by three prediction software (PolyPhen, SIFT and CADD). Cysts were observed in 2 of these subjects. Conclusion: Based on a survey of a large genetic database, LOF variants in FLCN are observed at a substantially higher frequency (0.0002-0.0004) than would be estimated from reported BHD cases. This may signify either that BHD syndrome is more much prevalent and is being vastly underdiagnosed, or that these variants are much less penetrant than previously thought. The higher prevalence of cystic disease among COPDGene subjects with less severe FLCN mutations supports the former possibility of under-diagnosis.