title: Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome.
abstract: Birt-Hogg-Dubé syndrome (BHD), a genodermatosis characterized by multiple hamartomas of the hair follicle (fibrofolliculoma), predisposes individuals to an increased risk of developing renal neoplasms and spontaneous pneumothorax. Previously, we localized the BHD locus (also known as FLCN) to chromosome 17p11.2 by linkage analysis and subsequently identified germline mutations in a novel gene in probands from eight of the nine families with BHD in our screening panel. Affected members of five of the families inherited an insertion/deletion of a cytosine in a C8 tract in exon 11. This mutation was also identified by exon 11 screening in probands from 22 of 52 additional families with BHD and therefore represents a hypermutable "hotspot" for mutation in BHD. Here, we screened the remaining 30 families from this large BHD cohort by direct sequence analysis and identified germline BHD mutations in 84% (51/61) of all families with BHD recruited to our study. Mutations were located along the entire length of the coding region, including 16 insertion/deletion, 3 nonsense, and 3 splice-site mutations. The majority of BHD mutations were predicted to truncate the BHD protein, folliculin. Among patients with a mutation in the exon 11 hotspot, significantly fewer renal tumors were observed in patients with the C-deletion than those with the C-insertion mutation. Coding-sequence mutations were not found, however, in probands from two large families with BHD whose affected members shared their family's BHD-affected haplotype. Of the 53 families with BHD whose members inherited either a germline mutation or the affected haplotype, 24 (45%) had at least one member with renal neoplasms. Three families classified with familial renal oncocytoma were identified with BHD mutations, which represents the first disease gene associated with this rare form of renal neoplasm. This study expands the BHD-mutation spectrum and evaluates genotype-phenotype correlations among families with BHD.
authors.affiliation: Basic Research Program, Science Applications International Corporation-Frederick Inc., Frederick, MD, USA. schmidtl@ncifcrf.gov
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nickerson
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Warren
authors.forename: Gladys M
authors.initials: GM
authors.lastname: Glenn
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Toro
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Merino
authors.forename: Maria L
authors.initials: ML
authors.lastname: Turner
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.forename: Nirmala
authors.initials: N
authors.lastname: Sharma
authors.forename: James
authors.initials: J
authors.lastname: Peterson
authors.forename: Patrick
authors.initials: P
authors.lastname: Morrison
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: McClellan M
authors.initials: MM
authors.lastname: Walther
authors.forename: Berton
authors.initials: B
authors.lastname: Zbar
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
mesh_terms: D018249:Adenoma, Oxyphilic / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D005091:Exons; D005260:Female; D005787:Gene Frequency; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007438:Introns; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D009679:Nuclear Family; D018579:Patient Selection; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D013577:Syndrome; D025521:Tumor Suppressor Proteins
chemical_list: C476078:FLCN protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins