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. 2022 Sep;24(9):1857-1866.
doi: 10.1016/j.gim.2022.05.006. Epub 2022 May 31.

Frequency of truncating FLCN variants and Birt-Hogg-Dubé-associated phenotypes in a health care system population

Juliann M Savatt  1 , Hermela Shimelis  2 , Andres Moreno-De-Luca  3 , Natasha T Strande  4 , Matthew T Oetjens  2 , David H Ledbetter  4 , Christa Lese Martin  4 , Scott M Myers  2 , Brenda M Finucane  2
Affiliations

Frequency of truncating FLCN variants and Birt-Hogg-Dubé-associated phenotypes in a health care system population

Juliann M Savatt et al. Genet Med. 2022 Sep.

Abstract

Purpose: Penetrance estimates of Birt-Hogg-Dubé syndrome (BHD)-associated cutaneous, pulmonary, and kidney manifestations are based on clinically ascertained families. In a health care system population, we used a genetics-first approach to estimate the prevalence of pathogenic/likely pathogenic (P/LP) truncating variants in FLCN, which cause BHD, and the penetrance of BHD-related phenotypes.

Methods: Exomes from 135,990 patient-participants in Geisinger's MyCode cohort were assessed for P/LP truncating FLCN variants. BHD-related phenotypes were evaluated from electronic health records. Association between P/LP FLCN variants and BHD-related phenotypes was assessed using Firth's logistic regression.

Results: P/LP truncating FLCN variants were identified in 35 individuals (1 in 3234 unrelated individuals), 68.6% of whom had BHD-related phenotype(s), including cystic lung disease (65.7%), pneumothoraces (17.1%), cutaneous manifestations (8.6%), and kidney cancer (2.9%). A total of 4 (11.4%) individuals had prior clinical BHD diagnoses.

Conclusion: In this health care population, the frequency of P/LP truncating FLCN variants is 60 times higher than the previously reported prevalence. Although most variant-positive individuals had BHD-related phenotypes, a minority were previously clinically diagnosed, likely because cutaneous manifestations, pneumothoraces, and kidney cancer were observed at lower frequencies than in clinical cohorts. Improved clinical recognition of cystic lung disease and education concerning its association with FLCN variants could prompt evaluation for BHD.

Keywords: Basilar cystic lung disease; Birt-Hogg-Dubé syndrome; FLCN; Health care system population; Variant prevalence.

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Conflict of interest statement

Conflict of Interest D.H.L is an employee of Unified Patient Network, Inc and scientific consultant for Natera, Inc; MyOme, Inc; and Seven Bridges Genomics. All other authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Pathogenic/Likely Pathogenic truncating variants in FLCN identified in the MyCode cohort.
Figure 2.
Figure 2.. Frequency of BHD-related phenotypes in the literature compared to that in MyCode patient-participants with truncating P/LP FLCN variants and in unique MyCode families.
See this image and copyright information in PMC

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References

    1. Birt AR, Hogg GR, Dubé WJ. Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons. Arch Dermatol 1977;113(12):1674–1677. - PubMed
    1. Schmidt LS, Linehan WM. Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome. Nat Rev Urol 2015;12(10):558–569. - PMC - PubMed
    1. Hasumi Y, Baba M, Ajima R, et al. Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proc Natl Acad Sci U S A 2009;106(44):18722–18727. - PMC - PubMed
    1. Baba M, Hong SB, Sharma N, et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A 2006;103(42):15552–15557. - PMC - PubMed
    1. Nickerson ML, Warren MB, Toro JR, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell 2002;2(2):157–164. - PubMed

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