The positional cloning of a human disease gene is a landmark event. Good examples are provided by Bardet–Biedl syndrome (BBS), for which several genes have recently been identified (see Highlights, July). But these landmarks have now assumed greater significance, because some cases of BBS seem to require at least three mutant alleles. As a clear-cut example of 'triallelic' inheritance, BBS might therefore provide some general lessons about the interaction between genes, and its influence on phenotype.

BBS is usually thought of as an autosomal-recessive disorder that is characterized by a broad and variable phenotype, involving retinal dystrophy, obesity, mental retardation, renal defects and polydactyly. BBS is also genetically heterogeneous — defects at several loci can cause the disease. So, when Katsanis et al. screened patients for mutations in two known BBS genes ( BBS2 and BBS6 ), it was no surprise to find mutations in these genes in only some of the patients. What was more surprising was that some affected individuals carried three mutant alleles — for example, two in BBS2 and one in BBS6.

The authors propose that BBS is inherited, at least in some individuals, in a triallelic fashion, although further BBS genes will need to be identified to determine the generality of this observation. In an accompanying Perspective, Arthur Burghes and colleagues, describe BBS inheritance as autosomal recessive with a modifier of penetrance, and liken BBS to other disorders in which modifier loci have been identified. However these unexpected findings are described, BBS provides a clear example of a phenotype that is determined by interactions between a small number of genes. BBS inheritance therefore lies somewhere between Mendelian and polygenic. As researchers move towards a more molecular understanding of BBS pathology, this disorder will become a valuable source of information about potential genetic interactions in more complex genetic disease.