Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder charact erized by multiple clinical features that include pigmentary retinal dystro phy, polydactyly, obesity, developmental delay, and renal defects. BBS is c onsidered an autosomal recessive disorder, and recent positional cloning ef forts have identified two BBS genes (BBS2 and BBS6). We screened our cohort of 163 BBS families for, mutations in both BBS2 and BBS6 and report the pr esence of three mutant alleles in affected individuals in four pedigrees. I n addition, we detected unaffected individuals in two pedigrees who carry t wo BBS2 mutations but not a BBS6 mutation. We therefore propose that BBS ma y not be a single-gene recessive disease but a complex trait requiring thre e mutant alleles to manifest the phenotype. This triallelic model of diseas e transmission may be important in the study of both Mendelian and multifac torial disorders.