Submission Details

The BBS1 gene was first reported in relation to Bardet-Biedl syndrome in a 2002 study of affected individuals with a combination of retinal and extraocular features (PMID: 12118255). Subsequent publications have established that cases diagnosed with Bardet-Biedl syndrome 1 exhibit retinal disease as the most penetrant feature, characterized by retinal dystrophy, pigmentary retinopathy, reduced visual acuity, night blindness, peripheral visual field constriction, reduced or absent rod and cone electroretinogram responses, attenuation of retinal blood vessels, optic disc pallor, and/or nystagmus. These phenotypes are generally accompanied by diverse extraocular features such as obesity, polydactyly, renal abnormalities including cysts, hypoplastic external genitalia in males, and/or intellectual disability. More recent publications have revealed that the spectrum of disease also includes cases diagnosed with juvenile onset retinitis pigmentosa, in which most or all extraocular features are absent (PMID: 23847139, PMID: 27032803). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic BBS1 loss of function) have been found to be consistent among patients diagnosed with either Bardet-Biedl syndrome 1 (MIM# 209900) or retinitis pigmentosa, while the phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic BBS1 variants have been lumped into a single disease entity, referred to as BBS1-related ciliopathy.

Nine suspected disease-causing variants have been scored as part of this curation (one nonsense, two frameshift, four affecting splicing, one missense, and one large insertion-deletion resulting in a frameshift), which have been collectively reported in twelve probands in five publications (PMID: 12118255, PMID: 23847139, PMID: 33169370, PMID: 19797195, PMID: 27032803). All of the probands scored in this curation harbored biallelic BBS1 variants. The mechanism of pathogenicity appears to be biallelic loss of BBS1 function conferred by null and/or hypomorphic variants. Only one relatively small family was found in the literature with at least three affected members (PMID: 33169370), and segregation evidence did not contribute to the scoring of this curation.

This gene-disease association is also supported by biochemical evidence that BBS1 encodes a component of the BBSome, a protein complex that functions in ciliogenesis and intraflagellar transport (PMID: 22072986). BBS1 co-immunoprecipitates with BBS4 (PMID: 17574030), and the genes encoding other BBSome components have similarly been asserted in connection with various monogenic forms of Bardet-Biedl syndrome, including BBS2 (PMID: 11285252), ARL6 (PMID: 15258860), BBS4 (PMID: 11381270), BBS5 (PMID: 15137946), MKKS (PMID: 10973238, PMID: 10973251), BBS7 (PMID: 12567324), and TTC8 (PMID: 14520415). Chlamydomonas with partial deletion of BBS1 are unable to perform light-responsive movement (PMID: 20038682), while Zbbs1 knockdown in zebrafish disrupts ciliary beat frequency and triggers cyst formation in the pronephritic kidney (PMID: 24069149). Biallelic disruption of Bbs1 in mice has been studied in ciliated tissues of the brain, where it causes cilia to aberrantly accumulate or exclude various G-protein-coupled receptors (PMID: 36699005). Homozygous knock-in of a missense variant from human patients into mouse Bbs1 recapitulates both retinal and syndromic features from the human disease state, including abnormal dark-adapted electroretinogram, photoreceptor layer loss on optical coherence tomography, obesity, and male reproductive abnormalities (PMID: 18032602).

In summary, BBS1 is definitively associated with BBS1-related ciliopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on December 7th, 2023 (SOP Version 10).