Submission Details

The BBS9 gene (also called PTHB1) was originally identified by differential display analysis as a gene down-regulated by parathyroid hormone (PTH) in an osteoblastic cell line. Multiple alternatively spliced isoforms of PTHB1 are expressed in different tissues. Independent genetic studies, involving comparative mapping and gene expression analysis, led to the identification of PTHB1 as a novel gene associated with Bardet-Biedl syndrome (Nishimura et al., 2005, PMID: 16380913).

Bardet-Biedl syndrome 9 (MIM#: 615986) is typically an autosomal recessive disorder that exhibits variable expressivity and phenotypes including retinopathy, mental retardation, obesity, polydactyly, and renal abnormalities. The main alterations observed are nonsense variants along the gene (34%). Additionally, frameshift, splice site variants and large deletions, all leading to a truncated protein, summarize up to 80% of all known variants. Consequently, the main disease causing mechanism may be a loss of function of the BBS9 protein (PMID: 33771153, PMID: 34212515, PMID: 32165602, PMID: 26846096).

The reported variant spectrum in BBS9 includes 21 missense, 49 nonsense, 35 frameshift, 33 splice defects, and 4 exon deletions (PMID: 33771153). Altogether, variants in BBS9 account for ∼6% of BBS cases. Because the published cases exhibit a recessive mode of inheritance and share overlapping retinal phenotypes consistent with a single spectrum of disease, this curation has lumped these cases into a single disease entity, BBS9-related ciliopathy.

This curation has collected data from 3 consanguineous families and 1 isolated individual with 4 unique variants (PMID: 33771153, PMID: 34212515, PMID: 32165602, PMID: 26846096). Additional experimental evidence was found in studies of expression, biochemical function and animal model systems (PMID: 22479622, PMID: 16380913). Although the BBS9 protein has been shown to be a part of the Bardet-Biedl syndrome protein complex (BBSome) core, its precise physiological function has not been delineated, and the mechanism of disease pathogenesis caused by BBS9 variants remains poorly understood. The BBSome is an octameric complex that transports membrane proteins into the primary cilium signaling organelle in eukaryotes and is implicated in human disease. The 99-kDa human BBS9 protein is one of the eight BBSome components. It is composed of four structured domains, including a β-stranded N-terminal domain (PMID: 26085087). Experimental studies in zebrafish have provided strong evidence in support of the role of BBS9 in cilia development as its morpholino-based knockdown results in a BBS-like syndromic phenotype in zebrafish. An orthologous human BBS9 mRNA rescued the morphant phenotype, while a mutant mRNA failed to provide functional complementation, suggesting an evolutionary conservation of BBS9 function (PMID: 16380913, PMID: 22479622).

In summary, BBS9 is definitively associated with BBS9-related ciliopathy, in which one of the major features is retinal cone-rod dystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Retina Gene Curation Expert Panel on August 3rd, 2023 (ClinGen Gene Clinical Validity Framework SOP verison 9).