Abstract
Birt–Hogg–Dubé syndrome (BHDS, MIM #135150), caused by germline mutations of FLCN gene, is a rare autosomal dominant inherited disorder characterized by skin fibrofolliculomas, renal cancer, pulmonary cysts and spontaneous pneumothorax. The syndrome is considered to be under-diagnosed due to variable and atypical manifestations. Herein we present a BHDS family. Targeted next generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) revealed a novel FLCN intragenic deletion spanning exons 10-14 in four members including the proband with pulmonary cysts and spontaneous pneumothorax, one member with suspicious skin lesions and a few pulmonary cysts, as well as two asymptomatic family members. In addition, a linkage analysis further demonstrated one member with pulmonary bullae to be a BHDS-ruled-out case, whose bullae presented more likely as an aspect of paraseptal emphysema. Furthermore, the targeted NGS and MLPA data including our previous and present findings were reviewed and analyzed to compare the advantages and disadvantages of the two methods, and a brief review of the relevant literature is included. Considering the capability of the targeted NGS method to detect large intragenic deletions as well as determining deletion junctions, and the occasional false positives of MLPA, we highly recommend targeted NGS to be used for clinical molecular diagnosis in suspected BHDS patients.
Highlights
Birt–Hogg–Dubé syndrome (BHDS, MIM #135150), caused by germline mutations of FLCN gene, is a rare autosomal dominant inherited disorder characterized by skin fibrofolliculomas, renal cancer, pulmonary cysts and spontaneous pneumothorax (Roth et al, 1993; Birt et al, 1977; Nickerson et al, 2002)
We report a novel FLCN intragenic deletion spanning exons 10–14 segregated in a BHDS family
The deletion was detected in two affected members (II-1 and II-2) as well as two asymptomatic carriers (Figure 1A), who were subsequently diagnosed with BHDS
Summary
Birt–Hogg–Dubé syndrome (BHDS, MIM #135150), caused by germline mutations of FLCN gene, is a rare autosomal dominant inherited disorder characterized by skin fibrofolliculomas, renal cancer, pulmonary cysts and spontaneous pneumothorax (Roth et al, 1993; Birt et al, 1977; Nickerson et al, 2002). Multiple and bilateral pulmonary cysts are the most common manifestation of BHDS and can be observed in more than 80% of BHDS patients (Zbar et al, 2002; Schmidt et al, 2005; Toro et al, 2007; Agarwal et al, 2011) They could exhibit a pneumothorax dominant phenotype with no or reduced penetrance of the skin or renal manifestations (Ren et al, 2008). As phenotype analysis in this family could not exclude the possibility of BHDS, we performed a targeted NGS in twelve suspect BHDS patients without any pathogenic mutation of FLCN gene including the proband. Detailed methods and a visualized flow chart of deletion detection and precise breakpoints determination (Supplementary Figure 2) were available in the Supplementary Material
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