Triallelic inheritance: a bridge between Mendelian and multifactorial traits

Abstract

The increasing identification of disease genes is revealing a growing number of traits that fail to conform to traditional Mendelian paradigms, thereby creating new challenges to both genetic investigators and clinicians. Bardet‐Biedl syndrome (BBS) is one such disorder that has helped to define ‘oligogenic’ inheritance, a term that implies that some diseases are not inherited as simple single‐gene Mendelian disorders and yet are not classic complex traits, but rather fit a model in which mutations in a small number of genes may interact genetically to manifest the phenotype. BBS is a pleiotropic disorder characterized by post‐natal obesity, post‐axial polydactyly, and progressive retinal dystrophy. Eight BBS loci have been identified to date and six of these genes have been cloned. Mutation analysis of these BBS genes in a cohort of patients has led to the description of the novel phenomenon of ‘triallelic inheritance,’ wherein families were identified in which three mutations from genes at two different BBS loci segregate with expression of the disease. Modeling the cooperative ability of alleles of different genes at distinct loci to give rise to a particular phenotype will facilitate the understanding of complex multifactorial and polygenic traits.