BBS7

Abstract: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous ciliopathy. Although nine BBS genes have been cloned, they explain only 40-50% of the total mutational load. Here we report a major new BBS locus, BBS10, that encodes a previously unknown, rapidly evolving vertebrate-specific chaperonin-like protein. We found BBS10 to be mutated in about 20% of an unselected cohort of families of various ethnic origins, including some families with mutations in other BBS genes, consistent with oligogenic inheritance. In zebrafish, mild suppression of bbs10 exacerbated the phenotypes of other bbs morphants.

Abstract: Bardet-Biedl syndrome (BBS) is a defining ciliopathy, notable for extensive allelic and genetic heterogeneity, almost all of which has been identified through sequencing. Recent data have suggested that copy-number variants (CNVs) also contribute to BBS. We used a custom oligonucleotide array comparative genomic hybridization (aCGH) covering 20 genes that encode intraflagellar transport (IFT) components and 74 ciliopathy loci to screen 92 unrelated individuals with BBS, irrespective of their known mutational burden. We identified 17 individuals with exon-disruptive CNVs (18.5%), including 13 different deletions in eight BBS genes (BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, BBS9, and NPHP1) and a deletion and a duplication in other ciliopathy-associated genes (ALMS1 and NPHP4, respectively). By contrast, we found a single heterozygous exon-disruptive event in a BBS-associated gene (BBS9) in 229 control subjects. Superimposing these data with resequencing revealed CNVs to (1) be sufficient to cause disease, (2) Mendelize heterozygous deleterious alleles, and (3) contribute oligogenic alleles by combining point mutations and exonic CNVs in multiple genes. Finally, we report a deletion and a splice site mutation in IFT74, inherited under a recessive paradigm, defining a candidate BBS locus. Our data suggest that CNVs contribute pathogenic alleles to a substantial fraction of BBS-affected individuals and highlight how either deletions or point mutations in discrete splice isoforms can induce hypomorphic mutations in genes otherwise intolerant to deleterious variation. Our data also suggest that CNV analyses and resequencing studies unbiased for previous mutational burden is necessary to delineate the complexity of disease architecture.

Abstract: Bardet-Biedl syndrome (BBS) is a recessive genetic disease causing multiple organ anomalies Most patients carry mutations in genes encoding for the subunits of the BBSome, an octameric ciliary transport complex, or accessory proteins involved in the BBSome assembly or function BBS proteins have been extensively studied using in vitro, cellular, and animal models However, the molecular functions of particular BBS proteins and the etiology of the BBS symptoms are still largely elusive In this study, we applied a meta-analysis approach to study the genotype-phenotype association in humans using our database of all reported BBS patients The analysis revealed that the identity of the causative gene and the character of the mutation partially predict the clinical outcome of the disease Besides their potential use for clinical prognosis, our analysis revealed functional differences of particular BBS genes in humans Core BBSome subunits BBS2, BBS7, and BBS9 manifest as more critical for the function and development of kidneys than peripheral subunits BBS1, BBS4, and BBS8/TTC8, suggesting that incomplete BBSome retains residual function at least in the kidney

Abstract: The purpose of this overview is to increase the awareness of clinicians regarding the causes of Bardet-Biedl syndrome and related genetic counseling issues.The following are the goals of this overview: Goal 1 Describe the clinical characteristics of Bardet-Biedl syndrome. Goal 2 Review the genetic causes of Bardet-Biedl syndrome. Goal 3 Provide an evaluation strategy to identify the genetic cause of Bardet-Biedl syndrome in a proband (when possible). Goal 4 Review management of Bardet-Biedl syndrome. Goal 5 Inform genetic counseling of family members of an individual with Bardet-Biedl syndrome.