BBS2 was first reported in relation to autosomal recessive Bardet-Biedl Syndrome in 2001 (Nishimura et al., PMID: 11285252). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic BBS2 loss of function) have been found to be consistent among patients diagnosed with either Bardet-Biedl syndrome 2 (MIM#: 606151) or retinitis pigmentosa 74 (MIM#: 616562), while the phenotypic variability between the two groups of cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic BBS2 variants have been lumped into a single disease entity, referred to as BBS2-related ciliopathy.
Nine unique variants (two missense, three nonsense, one frameshift, and three splicing) that have been reported in thirteen probands in five publications (PMIDs: 11567139, 11285252, 24608809, 21052717, 33777945) are included in this curation. 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 biallelic loss-of-function.
This gene-disease association is also supported by data from ProteinAtlas that BBS2 is non-specifically expressed in the retina as well as many other tissues, consistent with the clinical heterogeneity of Bardet-Biedl syndrome (PMID: 28940711). Biochemical evidence indicates that the protein encoded by the BBS2 gene is a component of the BBSome, a protein complex that functions in ciliogenesis and intraflagellar transport (PMID: 22072986). Tandem affinity purification followed by mass spectrometry has shown that BBS2 forms a stable complex along with other proteins that are encoded by genes associated with Bardet-Biedl syndrome (BBS1, BBS4, BBS5, BBS7, BBS8, and BBS9, PMID: 17574030). BBS2 homozygous knockout zebrafish without a functional copy of BBS2 exhibit retinal degeneration and vision loss (PMID: 33324636). A Bbs2 null mouse model recapitulated even more of the features of human patients, including obesity, retinal degeneration, renal cysts, and male infertility (PMID: 15539463).
In summary, BBS2 is definitively associated with autosomal recessive BBS2-related ciliopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on March 7th, 2024 (SOP Version 10).
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