Abstract
BackgroundBirt-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.MethodsWe 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 resultsAmong 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.ConclusionsWe 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.
Highlights
Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant disorder, the main manifestations of which are fibrofolliculomas, renal tumors, pulmonary cysts and recurrent pneumothorax
It suggests that mutation analysis of the FLCN gene should be systematically conducted in patients with cystic lung diseases
Birt-Hogg-Dubé syndrome (BHD, OMIM #135150) is a rare autosomal dominant disorder, the main symptoms of which are multiple pulmonary cysts followed by recurrent pneumothorax, fibrofolliculomas, and renal cell carcinomas
Summary
Study population A total of 51 patients who had been receiving medical care at Peking Union Medical College Hospital (PUMCH) and who had pulmonary cysts in clinical diagnosis from January 2014 to February 2017 were included in the study. High-resolution computed tomography (HRCT) results of each patient were assessed by two pulmonary physicians independently. Those with radiology images highly suggestive of other diffuse cystic lung diseases were excluded; these diseases included lymphagioleiomyomatosis, light chain deposition disease, amyloidosis, infectious pneumocystis, tuberous sclerosis, lymphoid interstitial pneumonia and pulmonary Langerhans cell histiocytosis. All mutations were checked in the Human Gene Mutation Database, which is the gold standard resource for comprehensive data on published human inherited disease mutations Those that had not been previously reported are marked as novel mutations in this article. For those whose Sanger sequencing showed negative mutation results, a multiplex ligationdependent probe amplification (MLPA) test was applied. MLPA can be used to detect whole-exon deletions and duplications that are not detectable by traditional Sanger sequencing [20, 21]
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