Genotypic characteristics of Chinese patients with BHD syndrome and functional analysis of FLCN variants
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(2019) 14:223
RESEARCH
Open Access
Genotypic characteristics of Chinese patients with BHD syndrome and functional analysis of FLCN variants Keqiang Liu1†, Wenshuai Xu2†, Xinlun Tian2†, Meng Xiao1, Xinyue Zhao1, Qianli Zhang1, Tao Qu3, Jiaxing Song1, Yaping Liu1* , Kai-Feng Xu2* and Xue Zhang1
Abstract Background: Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant disease featured by lung cysts, spontaneous pneumothorax, fibrofolliculomas and renal tumors. The causative gene for BHDS is the folliculin (FLCN) gene and more than 200 mutations have been reported in FLCN, mostly truncating mutations. The aim of this study is to better characterize the clinical features and mutation spectrum of Chinese BHDS patients and to systematically evaluate the effects of non-truncating mutations on mRNA splicing pattern. Methods: We enrolled 47 patients from 39 unrelated families with symptoms highly suggestive of BHDS after informed consent and detailed clinical data were collected. Exon sequencing followed by multiplex ligationdependent probe amplification testing were applied for mutation screening. The effects of non-truncating mutations, including 15 missense mutations and 6 in-frame deletions, on mRNA splicing were investigated by minigene assays. Results: A total of 24 FLCN germline variants were found in 39 patients from 31 distinct families. Out of these patients, 100% (36/36) presented with lung cysts and 58.3% (21/36) had experienced spontaneous pneumothorax. Seventeen mutation carriers had skin lesions (47.2%, 17/36) and 9 (30%, 9/30) had kidney lesions including 8 with renal cysts and 1 with renal hamartoma. Among all detected variants 14 (58.3%, 14/ 24) were novel, including 11 variants classified to be pathogenic and 3 variants of uncertain significance. None of 21 non-truncating mutations changed the mRNA splicing pattern of minigenes. Conclusions: We found different clinical features of Chinese BHDS patients compared with Caucasians, with more lung cysts and pneumothorax but fewer skin lesions and malignant renal cancer. Chinese patients with BHDS also have a different mutation spectrum from other races. Non-truncating mutations in FLCN did not disrupt mRNA splicing pattern, in turn supporting the hypothesis that these mutations impair folliculin function by disrupting the stability of the FLCN gene product. Keywords: Birt-Hogg-Dubé syndrome (BHDS), FLCN, Mutation spectrum, Clinical manifestations, Minigene assay, Non-truncating mutation
* Correspondence: [email protected]; [email protected] † Keqiang Liu, Wenshuai Xu and Xinlun Tian contributed equally to this work. 1 McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China 2 Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China Full list of author information is av
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