title: BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports.
abstract: BACKGROUND
  Birt-Hogg-Dubé syndrome (BHDS) (MIM 135150) is an autosomal dominant predisposition to the development of follicular hamartomas (fibrofolliculomas), lung cysts, spontaneous pneumothorax, and kidney neoplasms. Germline mutations in BHD are associated with the susceptibility for BHDS. We previously described 51 BHDS families with BHD germline mutations.
  
  
  OBJECTIVE
  To characterise the BHD mutation spectrum, novel mutations and new clinical features of one previously reported and 50 new families with BHDS.
  
  
  METHODS
  Direct bidirectional DNA sequencing was used to screen for mutations in the BHD gene, and insertion and deletion mutations were confirmed by subcloning. We analysed evolutionary conservation of folliculin by comparing human against the orthologous sequences.
  
  
  RESULTS
  The BHD mutation detection rate was 88% (51/58). Of the 23 different germline mutations identified, 13 were novel consisting of: four splice site, three deletions, two insertions, two nonsense, one deletion/insertion, and one missense mutation. We report the first germline missense mutation in BHD c.1978A>G (K508R) in a patient who presented with bilateral multifocal renal oncocytomas. This mutation occurs in a highly conserved amino acid in folliculin. 10% (5/51) of the families had individuals without histologically confirmed fibrofolliculomas. Of 44 families ascertained on the basis of skin lesions, 18 (41%) had kidney tumours. Patients with a germline BHD mutation and family history of kidney cancer had a statistically significantly increased probability of developing renal tumours compared to patients without a positive family history (p = 0.0032). Similarly, patients with a BHD germline mutation and family history of spontaneous pneumothorax had a significantly increased greater probability of having spontaneous pneumothorax than BHDS patients without a family history of spontaneous pneumothorax (p = 0.011). A comprehensive review of published reports of cases with BHD germline mutation is discussed.
  
  
  CONCLUSIONS
  BHDS is characterised by a spectrum of mutations, and clinical heterogeneity both among and within families.
authors.affiliation: Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Executive Plaza South, Room 7012, Rockville, MD 20892-7231, USA. torojo@mail.nih.gov
authors.forename: J R
authors.initials: JR
authors.lastname: Toro
authors.forename: M-H
authors.initials: MH
authors.lastname: Wei
authors.forename: G M
authors.initials: GM
authors.lastname: Glenn
authors.forename: M
authors.initials: M
authors.lastname: Weinreich
authors.forename: O
authors.initials: O
authors.lastname: Toure
authors.forename: C
authors.initials: C
authors.lastname: Vocke
authors.forename: M
authors.initials: M
authors.lastname: Turner
authors.forename: P
authors.initials: P
authors.lastname: Choyke
authors.forename: M J
authors.initials: MJ
authors.lastname: Merino
authors.forename: P A
authors.initials: PA
authors.lastname: Pinto
authors.forename: S M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: L S
authors.initials: LS
authors.lastname: Schmidt
authors.forename: W M
authors.initials: WM
authors.lastname: Linehan
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins