Submission Details

The BBS10 gene was first reported in relation to autosomal retinal dystrophy in 2006 (Stoetzel et al., 2006, PMID: 16582908) as part of the clinical presentation of the multisystem ciliopathy known as Bardet-Beidl syndrome; BBS10 variants appear to account for 20% of disease burden in Bardet-Biedl syndrome, depending on the ancestral background. The predominant retinal phenotype is BBS10-related rod-cone dystrophy. BBS10-related cone and cone-rod dystrophy have also been reported (PMIDs: 34940782, 36084042). We find that BBS10-related disease is inherited in an autosomal recessive pattern, with biallelic BBS10 variants causing retinal dystrophy in the context of Bardet-Biedl syndrome, which may include obesity, polydactyly, renal symptoms, intellectual disability and genital abnormalities. While an affected individual’s symptoms may be variable, all reported cases to date appear to have retinal dystrophy. Because the cases with variable severity of syndromic presentation, including non-syndromic cases (PMID: 36084042), all exhibit a recessive mode of inheritance and share overlapping retinal phenotypes consistent with a single spectrum of disease, these cases have been lumped into a single disease entity, BBS10-related ciliopathy.

This curation has scored twelve suspected disease-causing variants (8 predicted null and 6 missense variants) that have been reported in 12 probands in 12 publications (PMIDs: 16582908, 26082521, 28143435, 37031301, 33572860, 34940782, 17106446, 26518167, 20472660, 36084042). Homozygous nonsense variants in families from multiple countries were included in the curation (PMIDs: 28143435, 17106446, 26518167) from both consanguineous and non-consanguineous families. However, missense variants have also been associated with BBS-related disease in multiple publications (PMIDs: 16582908, 26082521, 20472660). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

The mechanism of pathogenicity appears to be loss of function, as multiple nonsense or frameshift variants resulting in BBS10-related disease are described in the literature (PMIDs: 28143435, 17106446, 26518167). However, missense, pre-coding and splicing variants are also reported to be associated with disease (PMIDs: 16582908, 36084042, 26082521, 20472660). Genotype-phenotype correlations between retinal dystrophy subtype (rod-cone vs. cone-rod) and variant type have not been established.

The BBS10 protein is a charperonin-like molecule that mediates assembly of the BBSome, a key player in molecular transport for the cilium. Multiple BBS10 animal models support the gene-disease correlation. A seminal paper (PMID: 16582908) has documented that knockdown of BBS10 in zebrafish embryos results in axial shortening, consistent with the syndromic phenotype seen in patients harboring disease-causing variants. A mouse knockout model of disease demonstrated severe retinal degeneration and retinal thinning (PMIDs: 26273430, 36125046). In cell culture models, BBS10 interacts with other known retinal dystrophy-causing gene products, including BBSome component BBS6 (PMID: 20080638). Multiple cell culture models reinforce the gene-disease relationship, including patient-derived cells that display ciliary defects, rescued by overexpression of wild type BBS10 (PMID: 33630762).

In summary, BBS10 is definitively associated with BBS10-related ciliopathy. While disease-causing variants are largely associated with rod-cone dystrophy in the context of Bardet-Beidl syndrome, other BBS10-related phenotypes have also been described, including cone-rod dystrophy. The association with retinal dystrophy has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This definitive classification has been approved by the ClinGen Retina GCEP on August 3rd, 2023 (SOP Version 9).