Type of mutations
BBS10is a 2 exons gene located on chromosome 12q21.2. Although additional 25 genes can be responsible of BBS, mutations in BBS10represents a major locus for BBS, accounting for approximately 20% of cases. Homozygous or compound heterozygous BBS10mutations cause the syndrome. Missense mutations and truncating mutations have been described. Given the founder effect, the p.C91Lfs*5 mutations is one of the most common in Northern Europe.
Suspected pathophysiologic mechanism
BBS10 is a chaperonin like protein assisting BBSome formation. The chaperonins-like proteins include also MKKS/BBS6 and BBS12 and mediate BBSome assembly in a multistep process.
BBSome is a multiprotein complex, formed by BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBIP10/BBS18, required for primary cilium (PC) biogenesis, homeostasis and intraflagellar trafficking. The PC is a microtubule-based cellular organelle playing a pivotal role in several signalling pathways and regulating multiple cellular functions. Disruption of PC homeostasis due to genetic mutations cause a number of rare clinical conditions known as ciliopathies, with overlapping phenotypes encompassing retinal degeneration, renal and developmental abnormalities. Molecular trafficking along the PC depends on the intraflagellar transport (IFT) machinery formed from two stable complexes, IFT-A and IFT-B. In the PC, the BBSome acts as an adaptor between the IFT machinery and membrane proteins, with and essential role in ciliary compartmentalization of signaling molecules. Mutations of BBS genes dramatically affects BBSome formation and/or activity, with consequent effects on ciliary trafficking and signaling pathways.
Besides their ciliary functions, BBSome components play extraciliary functions, including vesicular trafficking, cytoskeleton dynamics and gene expression. This wide range of functions may contribute to the complexity of BBS-related diseases.
Genotype-phenotype correlation
Genotype–phenotype correlation in Bardet-Biedl syndrome is made difficult by the unavailability of large cohort studies and the genetic heterogeneity of the disease. Nevertheless, patients with mutations in chaperonin-encoding BBS genes have a worse phenotype than BBS3/ARL6mutated, comparable to mutations in BBSome. Studies described a worse renal phenotype in case of BBS10(but also BBS2and BBS12) mutations compared with BBS1mutations. In addition, patients with mutations in BBS10(or BBS2) have higher frequency of polydactyly than BBS1mutated patients.
Genetic testing
Possible molecular diagnostic approaches to confirm the diagnosis include:
• Next generation sequencing, performing whole exome sequencing (WES) or using multi-gene panels which include BBS10and the other genes responsible of BBS.
• BBS10Sanger sequencing (single-gene testing) in case of a known mutation in family.
BBS10