Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive ciliopathy presenting with retinal dystrophy, postaxial polydactyly, obesity, renal insufficiency, hypogonadism, and learning difficulties. Biallelic variants in the BBS2 gene (HGNC:967) have been implicated in BBS (MONDO:0015229), with multiple reports across diverse populations.
The overall gene–disease relationship between BBS2 and Bardet-Biedl syndrome is classified as Strong. Ten unrelated probands have been reported with biallelic BBS2 variants across ethnically distinct cohorts (PMID:18319026, PMID:20618352, PMID:26078953, PMID:37003573, PMID:37116049, PMID:39175229). Segregation of pathogenic alleles was confirmed in 5 additional affected relatives. Functional assays in cell and iPSC models, together with studies of IFT–BBSome interactions, corroborate the pathogenic role of BBS2 variants.
Inheritance of BBS2 variants follows an autosomal recessive pattern. Segregation analysis demonstrated co-segregation of disease phenotypes with biallelic BBS2 variants in multiple families (5 affected relatives). Case reports encompass 10 index patients carrying homozygous or compound heterozygous alleles, including splice site mutations (c.472-2A>G (PMID:20618352)), frameshift alleles (c.563del (p.Ile188ThrfsTer13)), and nonsense variants (c.1932T>G (p.Tyr644Ter) (PMID:26078953)). The spectrum spans at least 6 nonsense/frameshift, 3 canonical splice, and 1 missense variant (c.443A>T (p.Asn148Ile) (PMID:33688495)). A founder splice variant, c.472-2A>G, is recurrent in the Hutterite population.
Pathogenic BBS2 alleles lead to loss of BBSome function and defective ciliary trafficking, consistent with a haploinsufficiency mechanism in homozygous or compound heterozygous states. Visible immunoprecipitation and cell-based assays demonstrate that BBS2 interacts with IFT-B components to mediate export of GPR161 from cilia, and that disruption of this interaction impairs Hedgehog signaling (PMID:31471295). Minigene splicing assays confirmed aberrant exon usage for splicing variants. Patient-derived iPSC lines carrying the c.534+1G>T mutation retain pluripotency and allow in vitro modeling of BBS2 deficiency (PMID:34364070).
Heterozygous carriers of BBS2 mutations do not exhibit increased risk of obesity, hypertension, or renal disease, arguing against dominant or triallelic effects in unaffected relatives (PMID:19367329). No studies have refuted the association of biallelic BBS2 variants with BBS.
Biallelic loss-of-function variants in BBS2 are robustly associated with Bardet-Biedl syndrome, supported by genetic segregation in multiple families and concordant functional data demonstrating disrupted ciliary trafficking. The variant spectrum includes recurrent founder alleles and diverse truncating and splice mutations across populations. Comprehensive BBS2 testing should be incorporated into diagnostic panels for early detection and genetic counseling.
Key Take-home: BBS2 genetic testing reliably confirms autosomal recessive Bardet-Biedl syndrome, guiding clinical management and family planning.
Gene–Disease AssociationStrong10 probands, segregation in 5 affected relatives, concordant functional data Genetic EvidenceStrong10 unrelated probands with biallelic BBS2 variants including homozygous and compound heterozygous loss-of-function and splice alleles; autosomal recessive inheritance; 5 additional segregations Functional EvidenceModerateIFT-B–BBSome interaction studies and splicing/minigene assays concordantly demonstrate BBS2 disruption of ciliary export and splicing defects; patient-derived iPSC models |