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.

Mutations in BHD and TP53 genes, but not in HNF1β gene, in a large series of sporadic chromophobe renal cell carcinoma

“…The study of hereditary kidney cancer syndromes has led to the identification of kidney cancer-related genes that are also involved in sporadic RCC. Recently, germline BHD mutations were found in patients with Birt -Hogg -Dubé (BHD) syndrome (Nickerson et al, 2002), and a diverse spectrum of renal tumours have been described with somatic inactivation of BHD reported in BHD-related renal tumours (Khoo et al, 2002;Schmidt et al, 2005;Vocke et al, 2005). BHD promoter methylation has been reported in a subset of sporadic clear cell and chromophobe RCC, but somatic mutation of BHD in sporadic cases is rare (da Silva et al, 2003;Khoo et al, 2003).…”

A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene

“…Around 85% of patients clinically affected by BHD are found to have a germline FLCN mutation detected by sequencing (Nickerson et al, 2002;Schmidt et al, 2005).…”

“…The database lists previously published point mutations, deletions, duplications and splice site mutations in the FLCN gene (Bessis et al, 2006;Cho et al, 2008;Frohlich et al, 2008;Gad et al, 2007,Graham et al, 2005Gunji et al, 2007;Imada et al, 2009;Kawasaki et al, 2005;Khoo et al, 2002;Kim et al, 2008;Lamberti et al, 2005;Leter et al, 2008;Murakami et al, 2007;Nickerson et al, 2002;Painter et al, 2005;Palmirotta et al, 2008;Ren et al, 2008;Schmidt et al, 2005;Toro et al, 2008;van Steensel et al, 2007;Woodward et al, 2008). In addition 10 previously unpublished novel mutations/variants are included.…”

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

“…A total of 9 out of 19 mutations are frameshift: seven are small insertions or deletions (o5 bp), one is a deletion of 12 bp (c.1127_1131del), and one is a duplication of 12 bp (c.1166_1178dup) (Table 1). Generally, frameshift muta- tions occur in stretches of repetitive DNA nucleotide runs that probably cause slippage errors of the DNA polymerase, at the replication fork [Lovett, 2004;Schmidt et al, 2005]. IKBKG exon 10 is particularly rich in mononucleotide tracts of cytosines (Fig.…”