Ray Anindita, Chattopadhyay Esita, Singh Richa, Ghosh Saurabh, Bera Arnab, Sarma Mridul, Munot Mahavir, Desai Unnati, Rajan Sujeet, Prabhudesai Pralhad, Prakash Ashish K, Roy Chowdhury Sushmita, Bhowmick Niladri, Dhar Raja, Udwadia Zarir F, Dey Atin, Mitra Subhra, Joshi Jyotsna M, Maitra Arindam, Roy Bidyut
Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Orphanet J Rare Dis. 2022 Apr 27;17(1):176. doi: 10.1186/s13023-022-02326-5.
Birt-Hogg-Dubé syndrome (BHDS) is a rare monogenic condition mostly associated with germline mutations at FLCN. It is characterized by either one or more manifestations of primary spontaneous pneumothorax (PSP), skin fibrofolliculomas and renal carcinoma (chromophobe). Here, we comprehensively studied the mutational background of 31 clinically diagnosed BHDS patients and their 74 asymptomatic related members from 15 Indian families.
Targeted amplicon next-generation sequencing (NGS) and Sanger sequencing of FLCN in patients and asymptomatic members revealed a total of 76 variants. Among these variants, six different types of pathogenic FLCN mutations were detected in 26 patients and some asymptomatic family members. Two of the variants were novel mutations: an 11-nucleotide deletion (c.1150_1160delGTCCAGTCAGC) and a splice acceptor mutation (c.1301-1G > A). Two variants were Clinvar reported pathogenic mutations: a stop-gain (c.634C > T) and a 4-nucleotide duplication (c.1329_1332dupAGCC). Two known variants were: hotspot deletion (c.1285delC) and a splice donor mutation (c.1300 + 1G > A). FLCN mutations could not be detected in patients and asymptomatic members from 5 families. All these mutations greatly affected the protein stability and FLCN-FNIP2 interaction as observed by molecular docking method. Family-based association study inferred pathogenic FLCN mutations are significantly associated with BHDS.
Six pathogenic FLCN mutations were detected in patients from 10 families out of 15 families in the cohort. Therefore, genetic screening is necessary to validate the clinical diagnosis. The pathogenic mutations at FLCN affects the protein-protein interaction, which plays key roles in various metabolic pathways. Since, pathogenic mutations could not be detected in exonic regions of FLCN in 5 families, whole genome sequencing is necessary to detect all mutations at FLCN and/or any undescribed gene/s that may also be implicated in BHDS.
Birt-Hogg-Dubé综合征（BHDS）是一种罕见的单基因疾病，主要与卵泡抑素（FLCN）的种系突变相关。其特征为原发性自发性气胸（PSP）、皮肤纤维毛囊瘤和肾癌（嫌色细胞癌）中的一种或多种表现。在此，我们全面研究了来自15个印度家庭的31例临床诊断为BHDS的患者及其74名无症状相关亲属的突变背景。
对患者和无症状亲属进行靶向扩增子下一代测序（NGS）及FLCN的桑格测序，共发现76个变异。在这些变异中，在26例患者和一些无症状家庭成员中检测到6种不同类型的致病性FLCN突变。其中两个变异为新突变：一个11核苷酸缺失（c.1150_1160delGTCCAGTCAGC）和一个剪接受体突变（c.1301-1G＞A）。两个变异为Clinvar报告的致病性突变：一个无义突变（c.634C＞T）和一个4核苷酸重复（c.1329_1332dupAGCC）。两个已知变异为：热点缺失（c.1285delC）和一个剪接供体突变（c.1300+1G＞A）。在5个家庭的患者和无症状亲属中未检测到FLCN突变。通过分子对接方法观察到，所有这些突变均极大地影响了蛋白质稳定性及FLCN-FNIP2相互作用。基于家系的关联研究推断，致病性FLCN突变与BHDS显著相关。
在该队列的15个家庭中，有10个家庭的患者检测到6种致病性FLCN突变。因此，进行基因筛查以验证临床诊断很有必要。FLCN的致病性突变影响蛋白质-蛋白质相互作用，而这在各种代谢途径中起关键作用。由于在5个家庭的FLCN外显子区域未检测到致病性突变，因此有必要进行全基因组测序，以检测FLCN的所有突变和/或任何可能也与BHDS相关的未描述基因。
