Correspondence on “Frequency of truncating FLCN variants and Birt-Hogg-Dubé-associated phenotypes in a health care system population” by Savatt et al

Birt-Hogg-Dubé syndrome (BHD), caused by loss-of-function variants in the FLCN gene, is associated with an increased risk of pneumothorax, fibrofolliculomas, and renal cell carcinoma. The prevalence of BHD has previously been estimated to be 1 in 200,000 individuals. 1 Lertsburapa T. Birt-Hogg-Dubé syndrome. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=122Date: 2008 Date accessed: July 22, 2022 Google Scholar In a recent study based on the prevalence of pneumothorax in patients with BHD in comparison to the general population, the prevalence of BHD was estimated to be lower, at 2 cases per million. 2 Muller M.E. Daccord C. Taffé P. Lazor R. Prevalence of Birt-Hogg-Dubé syndrome determined through epidemiological data on spontaneous pneumothorax and Bayes theorem. Front Med (Lausanne). 2021; 8631168https://doi.org/10.3389/fmed.2021.631168 Crossref Scopus (12) Google Scholar In our national center of expertise for BHD in the Netherlands (Amsterdam UMC), until this year, approximately 450 patients with BHD have been tested positive for a pathogenic germline variant in FLCN. In a population of 17 million, this would translate to a prevalence of at least 1 in 38,000 individuals. Because not all Dutch patients are tested in our diagnostic laboratory and additional patients with BHD are diagnosed on a regular basis, we assume that many BHD cases still remain undiagnosed in our country. This indicates that either BHD is far more prevalent than assumed previously or it is more frequent in the Netherlands (eg, founder effect). In their recent study, Savatt et al 3 Savatt J.M. Shimelis H. Moreno-De-Luca A. et al. Frequency of truncating FLCN variants and Birt-Hogg-Dube-associated phenotypes in a health care system population. Genet Med. 2022; 24: 1857-1866https://doi.org/10.1016/j.gim.2022.05.006 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar reported the prevalence of truncating FLCN variants in a health care system population of 135,990 participants to be 1 in 3234 unrelated individuals. This indicates that the prevalence of BHD is approximately 60 times higher than is currently assumed in the literature. Interestingly, their observations highlight the critical role of and the opportunities provided by the integration of genomic and clinical data in allowing for personalized health care, prevention of disease, and improved diagnostics for patients with hereditary diseases. This study also raises several interesting questions on the prevalence, penetrance, and the natural history of BHD and other (rare) genetic diseases, which will likely be addressed in the coming years. Most participants (68.6%) carrying a truncating FLCN variant in the study by Savatt et al 3 Savatt J.M. Shimelis H. Moreno-De-Luca A. et al. Frequency of truncating FLCN variants and Birt-Hogg-Dube-associated phenotypes in a health care system population. Genet Med. 2022; 24: 1857-1866https://doi.org/10.1016/j.gim.2022.05.006 Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar had a phenotype consistent with BHD, whereas only 11% of individuals had been diagnosed with BHD. This shows that currently many patients with BHD remain undiagnosed, and stresses the need for increasing awareness, because renal screening is effective in preventing metastatic renal cell carcinoma. 4 Johannesma P.C. van de Beek I. van der Wel T.J.W.T. et al. Renal imaging in 199 Dutch patients with Birt-Hogg-Dubé syndrome: screening compliance and outcome. PLoS One. 2019; 14e0212952https://doi.org/10.1371/journal.pone.0212952 Crossref PubMed Scopus (15) Google Scholar Response to van Riel et alGenetics in MedicineVol. 25Issue 1PreviewLong before the availability of genomic sequencing technologies, initial descriptions of Mendelian disorders relied on clinical observation of individual patients and families. Medical dysmorphology and detailed pedigrees provided evidence for inheritance patterns while occasionally allowing a glimpse of variable expressivity and the milder end of the phenotypic spectrum for some disorders. Most well-established genetic syndromes were first discovered clinically in patients with classic manifestations and later matched to pathogenic variants in previously unknown genes. Full-Text PDF