A retrospective two centre study of Birt-Hogg-Dubé syndrome reveals a pathogenic founder mutation in FLCN in the Swedish population.

Kristina Lagerstedt-Robinson,Maritta Hellström Pigg,Emma Tham,Christos Aravidis,Izabella Baranowska Körberg,Anna Poluha,Erik Björck,Ylva Paulsson-Karlsson,Magnus Nordenskjöld,Stefanos Tsiaprazis,Maria Johansson-Soller,Obul Reddy Bandapalli

doi:10.1371/journal.pone.0264056

Abstract

Birt-Hogg-Dube syndrome (BHDS) (MIM: 135150) is a rare autosomal dominant disorder with variable penetrance, caused by pathogenic variants in the FLCN gene. Only a few hundreds of families have so far been described in the literature. Patients with BHDS present with three distinct symptoms: fibrofolliculomas, pneumothorax due to lung cyst formation, and increased lifetime risk of kidney tumours. The aim of the current study was to estimate the incidence of BHDS in the Swedish population and further describe the clinical manifestations and their frequency. Splice variant c.779+1G>T was the most common pathogenic variant, found in 57% of the families, suggesting this may be a founder mutation in the Swedish population. This was further investigated using haplotype analysis in 50 families that shared a common haplotype. Moreover, according to gnomAD the carrier frequency of the c.779+1G>T variant has been estimated to be 1/3265 in the Swedish population, however our data suggest that the carrier frequency in the Swedish population may be significantly higher. These findings should raise awareness among physicians of different specialties to patients presenting with fibrofolliculomas, pneumothorax and/or kidney tumours. We also stress the importance of consensus recommendations regarding diagnosis and clinical management of this, not that uncommon, syndrome.

Highlights

In late ‘70s three Canadian physicians introduced a novel genodermatosis syndrome characterized by the presence of multiple benign cutaneous neoplasms [1]
Our cohort consists of 278 individuals from 78 seemingly unrelated kindreds that were referred to the Department of Clinical Genetics, Akademiska University Hospital, Uppsala and Department of Clinical Genetics, Karolinska University Hospital, Stockholm between years 2007–2019, for clinical and genetic investigation of BHDS, or carriership analysis of a known variant in FLCN gene in their family
In total 278 individuals were tested for pathogenic variants in the FLCN gene between 2007 and 2019

Summary

Introduction

In late ‘70s three Canadian physicians introduced a novel genodermatosis syndrome characterized by the presence of multiple benign cutaneous neoplasms [1]. Birt-Hogg-Dubesyndrome (BHDS) (MIM# 135150), is an autosomal dominant disorder with unknown incidence. BHDS has as three main clinical features—the so called clinical triad; cutaneous hair follicle tumours, known as fibrofolliculomas or trichodiscomas, spontaneous recurrent pneumothorax in a pathological substrate of lung cysts and increased lifetime risk for kidney cancer [2,3,4,5,6,7,8]. Pathogenic founder mutation in FLCN causes Birt-Hogg-Dubè syndrom

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