A Novel FLCN Intragenic Deletion Identified by NGS in a BHDS Family and Literature Review

Abstract

Birt–Hogg–Dubé syndrome (BHDS, MIM #135150), caused by germline mutations of FLCN gene, is a rare autosomal dominant inherited disorder characterized by skin fibrofolliculomas, renal cancer, pulmonary cysts and spontaneous pneumothorax. The syndrome is considered to be under-diagnosed due to variable and atypical manifestations. Herein we present a BHDS family. Targeted next generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) revealed a novel FLCN intragenic deletion spanning exons 10-14 in four members including the proband with pulmonary cysts and spontaneous pneumothorax, one member with suspicious skin lesions and a few pulmonary cysts, as well as two asymptomatic family members. In addition, a linkage analysis further demonstrated one member with pulmonary bullae to be a BHDS-ruled-out case, whose bullae presented more likely as an aspect of paraseptal emphysema. Furthermore, the targeted NGS and MLPA data including our previous and present findings were reviewed and analyzed to compare the advantages and disadvantages of the two methods, and a brief review of the relevant literature is included. Considering the capability of the targeted NGS method to detect large intragenic deletions as well as determining deletion junctions, and the occasional false positives of MLPA, we highly recommend targeted NGS to be used for clinical molecular diagnosis in suspected BHDS patients.

Birt-Hogg-Dubé syndrome encountered at rare lung disease clinic in Anhui province, China

“…DNA Sequencing Analysis and Sequencing Analysis 5.2.0 software was used to analyze the sequencing results and using Sequencer 5.1 software package for comparative analysis. When a mutation could not be detected by direct sequencing, MLPA analysis and rapid NGS strategy of the FLCN gene were used based on our experts’ judgements (Prof. Shen and Dr. Yi) [ 18 ].…”

A Novel FLCN Variant in a Suspected Birt–Hogg–Dubè Syndrome Patient

“…Affected subjects also have a high risk of developing pulmonary cysts with associated spontaneous pneumothoraces, benign renal cysts, RCC, and other rare diseases (lipomas, parathyroid adenomas, parotid gland tumors, and colonic polyps/tumors) [1]. These clinical features are caused by germline mutations in the folliculin FLCN gene, a tumor suppressor which consists of 14 exons located on chromosome 17p11.23 [2]. Patients with PV and LPV FLCN variants have an increased risk of manifesting benign and malignant kidney disorders.…”

Case Report: A BRCA2 Mutation Identified Through Next-Generation Sequencing in a Birt–Hogg–Dubè Syndrome Family

“…Its clinical manifestation is generally associated with multiple pulmonary cysts, frequent spontaneous pneumothoraces (PNXs), benign skin hamartomas, cutaneous fibrofolliculomas, and renal tumors of different histological types ( 2 ). FLCN , located on chromosome 17p11.2, is currently the main gene known to be associated with BHDS ( 3 ). A broad range of mutations have been identified in FLCN gene, among which the majority of FLCN alterations identified in the germline of BHD patients are frameshift (insertion/deletion), nonsense, or splice-site mutations that generally produce unfunctional truncated FLCN proteins.…”