Clinical and genetic characteristics of chinese patients with Birt-Hogg-Dubé syndrome

Abstract

Background: Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder, the main manifestations of which are fibrofolliculomas, renal tumors, pulmonary cysts and recurrent pneumothorax. The known causative gene for BHD syndrome is the folliculin (FLCN) gene on chromosome 17p11.2. Studies of the FLCN mutation for BHD syndrome are less prevalent in Chinese populations than in Caucasian populations. Our study aims to investigate the genotype spectrum in a group of Chinese patients with BHD.

Methods: We enrolled 51 patients with symptoms highly suggestive of BHD from January 2014 to February 2017. The FLCN gene was examined using PCR and Sanger sequencing in every patient, for those whose Sanger sequencing showed negative mutation results, multiplex ligation-dependent probe amplification (MLPA) testing was conducted to detect any losses of large segments.

Main results: Among the 51 patients, 27 had FLCN germline mutations. In total, 20 mutations were identified: 14 were novel mutations, including 3 splice acceptor site mutations, 2 different deletions, 6 nonsense mutations, 1 missense mutation, 1 small insertion, and 1 deletion of the whole exon 8.

Conclusions: We found a similar genotype spectrum but different mutant loci in Chinese patients with BHD compared with European and American patients, thus providing stronger evidence for the clinical molecular diagnosis of BHD in China. It suggests that mutation analysis of the FLCN gene should be systematically conducted in patients with cystic lung diseases.

Keywords: Birt-Hogg-Dubé syndrome; FLCN; Mutation spectrum.

Fig. 1

Chest CT showing multiple thin-walled cysts in Patient B24

Fig. 2

Mutation spectrum of the FLCN gene responsible for BHD syndrome. Top of this figure: mutations identified in this study; Bottom of this figure: mutations identified in other studies as reviewed in Schmidt et al. [11], Furuya et al. [14], Zhang et al. [24], Rossing et al. [25]. Definitions of abbreviations: FS = frameshift; MS = missense; NS = nonsense; AAΔ, amino acid deletion inframe; pMet1? = proposed deletion of initiator codon; SS = splice site. ATG = initiator codon. CpG = putative promoter region. △E8 = whole exon 8 loss. Blue bar, intragenic deletion; Brown bar, intragenic duplication

Fig. 3

MLPA result of patient B17 showing loss of one copy of exon 8 of FLCN

Fig. 4

A picture showing Skin fibrofolliculinoma from one patient with BHD syndrome

Fig. 5

CT image showing renal cyst (arrow) in Patients B24