Folliculin (GENBANK accession #BC015687) was mapped to the BHD locus by a genome wide linkage analysis using polymorphic microsatellite markers in a large Swedish family with BHD Syndrome. This study found evidence of linkage to 17p12-q11.2 (Khoo et al., 2001). Subsequent haplotype analysis defined a candidate interval between the two flanking markers, D17S1791 and D17S798 (Khoo et al., 2001).
Schmidt et al. (2001) performed a genome wide scan in a large BHD kindred (172 members) and localised the gene to the pericentromeric region of 17p using linkage analysis. Two-point linkage analysis of eight additional families with BHD syndrome produced a maximum LOD score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of non-recombination as being within an interval of less than four cM between D17S1857 and D17S805 on chromosome 17p11.2.
The FLCN gene was ultimately identified when Nickerson et al. (2002) narrowed the critical region for the BHD locus to a 700-kb segment on 17p11.2. This genomic region contains a number of unstable low-copy number repeat elements which are subject to aberrant recombination events, causing deletions and duplications of the region (Stankiewicz and Lupski, 2002). Deletions within this region cause Smith-Magenis Syndrome (SMS) (Lucas et al., 2002), while duplications cause Charcot-Marie-Tooth Syndrome 1A (Roa et al., 1991). Interestingly, while the FLCN gene is often heterozygously deleted in SMS, patients do not seem to develop any of the symptoms of BHD (Truong et al., 2010). However, there has been one reported case of an SMS patient who suffered three pneumothoraces as a child (Truong et al., 2010).