The BBS12 gene was first identified as a disease-related locus in a 2007 study mapping the Bardet Biedl syndrome phenotype in two consanguineous families to a homozygous region on chromosome 4q26-q27 (Stoetzel C, et al., 2007, PMID: 17160889). BBS12 encodes a predicted chaperonin-like protein that exists specifically in vertebrates, and forms a complex with BBS6 and BBS10 that functions to mediate the assembly of the BBSome, a complex that performs vesicle transport to primary cilia and contributes to adipocyte differentiation (PMID: 17160889, PMID: 20080638).
Bardet-Biedl syndrome 12 (MIM#: 615989) is an autosomal recessive disorder characterized by variable expressivity and phenotypes such as retinal dystrophy, mental retardation, obesity, polydactyly, and/or renal abnormalities. The underlying mechanism is biallelic loss-of function variants in the BBS12 gene, with the mutation spectrum including predominantly missense, nonsense, and frameshift variants. This curation has collected and scored data from 2 consanguineous families and 1 isolated individual with 4 unique variants (PMID: 17160889, PMID: 20648243, PMID: 36574078). Additional genetic evidence was available in the literature but was not included as the maximum score for this category had already been reached.
Experimental evidence for the gene-disease relationship included a zebrafish model with suppression of bbs12 expression that exhibited defects in gastrulation and movement such as short body axis, broader somites, kinking of the notochord, and dorsal thinning, similar to the phenotypes caused by silencing of other BBS gene orthologs (PMID: 17160889). The participation of the BBS12 protein in a complex with BBS6 and BBS10 was also scored as protein interaction data (PMID: 20080638).
In summary, BBS12 is definitively associated with BBS12-related ciliopathy, in which one of the major features is retinal dystrophy. This 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 clinical validity classification was approved by the ClinGen Retina Gene Curation Expert Panel on January 4th, 2024 (SOP version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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