In search of triallelism in Bardet-Biedl syndrome

Abstract

Bardet-Biedl syndrome (BBS) is a model disease for ciliopathy in humans. The remarkable genetic heterogeneity that characterizes this disease is consistent with accumulating data on the interaction between the proteins encoded by the 14 BBS genes identified to date. Previous reports suggested that such interaction may also extend to instances of oligogenic inheritance in the form of triallelism which defies the long held view of BBS as an autosomal recessive disease. In order to investigate the magnitude of triallelism in BBS, we conducted a comprehensive analysis of all 14 BBS genes as well as the CCDC28B-modifier gene in a cohort of 29 BBS families, most of which are multiplex. Two in trans mutations in a BBS gene were identified in each of these families for a total of 20 mutations including 12 that are novel. In no instance did we observe two mutations in unaffected members of a given family, or observe the presence of a third allele that convincingly acted as a modifier of penetrance and supported the triallelic model of BBS. In addition to presenting a comprehensive genotype/phenotype overview of a large set of BBS mutations, including the occurrence of nonsyndromic retinitis pigmentosa in a family with a novel BBS9 mutation, our study argues in favor of straightforward autosomal recessive BBS in most cases.

Figure 1

Clinical photographs showing variable severity of BBS manifestations. Facies range from typical round (a–c) to near normal (d). (e) Severe brachydactyly. (f) Polydactylous hand with much milder degree of brachydactyly. Note the different level of placement of postaxial polydactyly in the same individual which is also shown in (g) and (h) but in a much milder form. (i) Severe form of male hypogenitalism.

Figure 2

Sequence chromatogram of all 12 novel BBS mutations. For each mutation, the upper panel represents the patient sequence with the mutation indicated by red asterisk and the lower panel is for comparison with normal control. Details of the RT-PCR experiment to show the exon loss in BBS9 and BBS13 are shown. Tiling PCR fragments confirmed that BBS9 exon 6 is deleted at the genomic level as part of a 6.7–7.2-kb deletion (Supplementary Figure S1). A pie chart is shown in the bottom to summarize the relative contribution of each BBS gene to the overall mutation pool of BBS in the study population.