Type of mutations
BBS1 is a 17 exons gene located on chromosome 11q13. Although additional 25 genes can be responsible of BBS, mutations in BBS1 cause about one-quarter of all cases of the disease.
Homozygous or compound heterozygous BBS1 mutations cause the syndrome. Missense mutations and truncating mutations have been described. The most common p.M390R variant has been reported in over 50% of BBS1 associate disease. Interestingly, it has been described in isolated forms of retinal degeneration and/or mild syndromic forms. Moreover, the c.1091 + 3G>C variant is described as a founder mutation in patients from Faroe Islands.
Suspected pathophysiologic mechanism
BBS1 forms with BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBIP10/BBS18 a multiprotein complex called BBSome, which is 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. In fact, BBS1 stabilizes the interaction between the BBSome and the IFT complex in preparation for retrograde transport. Besides their ciliary functions, BBS1 and other 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, several studies described a milder phenotype in patients with BBS1 variants compared to patients with mutations in other genes. This can be partially explained by the high prevalence of the hypomorphic BBS1 M390R variant, but also by the minimal effect of loss of BBS1 function on BBSome formation and stability, according to in vitro studies.
A recent metanalysis, conducted on 899 patients, suggest that among patients with mutations in BBSome components, those with mutations in BBS1 showed the lowest mean syndromic score, suggesting a milder phenotype and a lower frequency of kidney dysfunction in this setting.
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 BBS1 and the other genes responsible of BBS.
- BBS1 Sanger sequencing (single-gene testing) in case of a known mutation in family.
BBS1