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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 ligation-dependent 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.    Electronic supplementary material  The online version of this article (10.1186/s13023-019-1198-y) contains supplementary material, which is available to authorized users.

Genotypic characteristics of Chinese patients with BHD syndrome and functional analysis of FLCN variants