Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2

Abstract

Birt-Hogg-Dubé syndrome (BHD), an inherited autosomal genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal neoplasia, lung cysts, and spontaneous pneumothorax. To identify the BHD locus, we recruited families with cutaneous lesions and associated phenotypic features of the BHD syndrome. We performed a genomewide scan in one large kindred with BHD and, by linkage analysis, localized the gene locus to the pericentromeric region of chromosome 17p, with a LOD score of 4.98 at D17S740 (recombination fraction 0). Two-point linkage analysis of eight additional families with BHD produced a maximum LOD score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of nonrecombination as being within a <4-cM distance between D17S1857 and D17S805. One additional family, which had histologically proved fibrofolliculomas, did not show evidence of linkage to chromosome 17p, suggesting genetic heterogeneity for BHD. The BHD locus lies within chromosomal band 17p11.2, a genomic region that, because of the presence of low-copy-number repeat elements, is unstable and that is associated with a number of diseases. Identification of the gene for BHD may reveal a new genetic locus responsible for renal neoplasia and for lung and hair-follicle developmental defects.

Figure 1

Abridged pedigree and haplotype analysis of family 172. Skin (blue), lung (yellow), and kidney (red) phenotypes are indicated by the colored quadrants in the symbol for each individual. For linkage analysis, individuals with histologically positive fibrofolliculomas were considered to be affected. Marker order and genetic distance from the chromosome 17p telomere are indicated. Haplotypes were generated under the assumption that the smallest number of recombination events was present. Shaded boxes represent the affected haplotype commonly shared by family members with BHD. Genotypes in parentheses were inferred on the basis of data on relatives. Individual III-8 is an obligate carrier of the disease gene, because three of her children are positive for fibrofolliculomas. Individuals IV-9 and IV-11 are asymptomatic carriers of the affected haplotype. Critical recombinants IV-10 and III-6 define the BHD minimal region of linkage to an 8.5-cM distance between D17S918 and D17S1824.

Figure 2

Critical recombinants in families 210 and 230, which narrow the BHD nonrecombining region to <4.0 cM between D17S1857 and D17S805. A, Individual III-4 in family 210, who shows recombination at distal markers, D17S918, D17S953, and D17S1857 but shares the proximal affected haplotype (D17S740–D17S1824) with affected family members. Individual III-7 is an obligate carrier with an affected child, IV-3. Individual IV-2 is an asymptomatic carrier of the affected haplotype. B, Individual II-5 in family 230, who shares the distal affected haplotype with affected family members but shows recombination at proximal markers D17S805, D17S689, and D17S1824. The affected son, III-3, inherits the affected haplotype of his recombinant father. (For additional details, refer to the legend to fig. 1.)

Figure 3

Ideogram of chromosome 17, showing genetic-map location of microsatellite markers linked to the BHD locus. Map distances (in cM), from the 17p telomere, were obtained from the Marshfield map (see the Center for Medical Genetics, Marshfield Medical Research Foundation web site). The BHD interval, determined on the basis of recombination events, is flanked by D17S1857 and D17S805 (3.99 cM).