Bardet-biedl syndrome: New insights into ciliopathies and oligogenic traits

Bardet-Biedl syndrome [(BBS); OMIM 209900] is a clinically pleiotropic disorder transmitted primarily in an autosomal recessive fashion whose hallmarks include obesity, progressive retinal degeneration, polydactyly, hypogenitalism, cognitive impairment, and kidney dysplasia. The incidence of BBS has been estimated to be 1 in 150,000 in European populations but is much higher in some populations with a high level of consanguinity (the Middle East and North Africa, for example) or that are geographically isolated (Newfoundland). Since 1994, the use of homozygosity mapping in consanguineous BBS families has allowed the progressive recognition of a surprisingly high level of nonallelic genetic heterogeneity. Since the identification of the first gene in 2000 (BBS6, also called MKKS as it is mutated in the closely related McKusick-Kaufmann syndrome) mutations in BBS patients have been found in a total of 12 genes (BBS1-12) (1–5). Recent molecular evidence has revealed an unexpected connection between the BBS proteins and primary cilia (6), microtubule-based structures arising from the basal body that are notably involved as mechanosensors in kidney epithelium, in the organization of photoreceptor cells of the retina, and also in several morphogenetic signaling pathways, such as the planar cell polarity (PCP) noncanonical Wnt signaling pathway (7). This allowed the characterization of BBS as a ciliopathy, an expanding group of clinically distinct but overlapping disorders that includes autosomal dominant polycystic kidney disease, nephronophthisis, Alström syndrome (see Chapter 5.1), orofaciodigital syndrome type 1, and, most recently, Meckel syndrome and Joubert syndrome (8).